Global Effect of PEG-interferon-alpha and ribavirin on gene expression in PBMC in vitro.

 

Milton W. Taylor1, William M. Grosse1, Corneliu Sanda1 , Joel E. Schaley1, Xiaoning Wu 3, Shih-Chang Chien3, Fred Smith3, Thomas G. Wu3, Matthew Stephens2, Mary W. Ferris1, Jeanette N. McClintick2, Ronald E. Jerome2, Howard J. Edenberg2

 

1Department of Biology, Indiana University, Bloomington, Indiana, USA

2Department of Biochemistry and Molecular Biology and Center for Medical Genomics at Indiana University School of Medicine,

 Indianapolis, Indiana 46202-5122, USA

3Infectious Diseases Department, Roche Molecular Systems, Inc., Alameda, California 94501, USA

Correspondence should be addressed to M.W.T.; e-mail: taylor@indiana.edu

 

 

Running  title: Effect of IFN-alpha on gene expression in PBMC.

 

Abstract.

Utilizing oligonucleotide microarrays, we have examined the expression of 22,000 genes in peripheral blood cells treated with pegylated interferon-alpha2b (PEG-IFN-a) and ribavirin. Treatment with ribavirin had very little effect on gene expression, however treatment with PEG-IFN-a had a dramatic effect, modulating the expression of approximately 1000 genes (at P<0.001). In addition to genes previously reported to be induced by type I or type II interferons, many novel genes were found to be unregulated, including transcription factors such as ATF3, ATF4, properdin, a key regulator of the complement pathway, a homeobox gene (HESX1), and an RNA editing enzyme apobec3. Chemokines CXCL10 and 11 were up regulated whereas CXCL5 was down regulated. Cytokines IL-15 and IL-18 were also significantly induced whereas IL-1a and IL-1b were down regulated.  Most other interleukins were not affected.  The results of the microarrays were confirmed by kinetic real time PCR.  These data indicate that interferon treatment results in the up regulation of genes associated with the stress response, apoptosis, and signaling, while an equal number of genes are down regulated, including those associated with protein synthesis specific cytokines and chemokines and other biosynthetic functions.


INTRODUCTION.

 

The combination of pegylated interferon-alpha (PEG-IFN-a) and ribavirin is the current treatment of choice for chronic infections of hepatitis C. As part of a large study involving hepatitis C patients (http://www.edc.gsph.pitt.edu/virahepc/) we shall perform transcriptional microarrays with RNAs isolated from the peripheral blood monocytes (PBMC) of patients at different time points after treatment to discern possible differences in the gene response to IFN-ribavirin treatment between responders and non-responders. As a pilot study we examined the response of PBMC from healthy controls treated with this combination in vitro.  These data will be used in future to compare the response in vivo to the same treatment.  PBMC are being used in this study because of the lack of human liver tissue.

The mechanism whereby the combination of IFN-a and ribavirin results in complete clearance of the virus in some cases but only partial response in others is unknown.  In previous work1,2 we have examined the induction of serum cytokines in hepatitis C patients undergoing interferon/ribavirin treatment.  The only serum cytokines found to be elevated after treatment were the IL-1 agonist IL-1Ra and the pro-inflammatory cytokine IL-6. None of the more common cytokines such as IL-2, IL-4, IL-1, IFNg, or TNF-a were elevated in the serum of treated hepatitis C patients at any time following treatment, as measured by ELISA.  The induction of IL-1Ra and IL-6 was only transient, and in most cases had returned to normal (before treatment) levels by 24/48 hours.

In order to obtain a more thorough picture of the genes induced by the combined treatment of PEG-IFN-a and ribavirin, we treated peripheral blood mononuclear cells (PBMC) from normal individuals in culture for 24 hours with either PEG-IFN-a alone, ribavirin alone or the two in combination. The profile of genes being induced under these conditions was analyzed using Affymetrix GeneChip® HG-U133A microarrays.  These arrays contain oligonucleotides that report on the expression of approximately 22,000 human genes.  Both PEG-IFN-a and  combination treatment result in the induction or down regulation of a large number of genes (approximately 1000) at a significance level of p ≤ 0.001.

Four hundred and thirty nine unique sequences were induced by 24 hours treatment using a P value < 0.001. A subset of IFN related genes were selected for kinetic RT-PCR analysis.  The confirmatory results of kinetic RT-PCR in general matched the results obtained from the microarrays.  Four hundred and forty six unique sequences were down regulated by 24 hours in the presence of PEG-IFN and ribavirin, including a large number of ribosomal proteins and translation factors. Ribavirin by itself had essentially little effect on gene induction or down regulation. In this paper we report the identification of genes of biological importance, many not previously reported to be affected by interferon. An analysis of the response in human PBMC has not been documented before.

 

Methods.

Interferons.

Peg-intron (PEG-IFN-a2/b) was kindly provided by Schering-Plough (Kenilworth, N.J.) and used at 500 international units/ml when added to cultures of PBMC. Ribavirin (Schering-Plough, Kenilworth N.J.) was used at 10 mg/ml in the treatment of PBMC.

RNA purification

Whole blood (60 ml) was collected from healthy volunteers (4 individuals; one on two different days) into heparin-containing collection tubes.  Aliquots of blood were diluted in equal volumes (8 ml) of PBS and carefully layered over 10 ml Ficoll-Paque Plus (Amersham Pharmacia Biotech, Piscataway, NJ) gradients at room temperature.  The total PBMC were collected in PBS, washed once, and incubated at 37° C in the presence of CO2 for 24 hours in RPMI media (Invitrogen, Carlsbad, CA) containing 10% fetal bovine serum at 5x106 cells per ml. Samples were treated with either 500 units/ml PEG-IFN-a, 10 mg/ml ribavirin, a combination of both or incubated without interferon or ribavirin as control. RNA was extracted from 5x107 cells using Tri Reagent (Molecular Research Center, Inc., Cincinnati, OH) according to the manufacturer's specifications,  and finally the RNA was purified through an RNeasy column (Qiagen, Valencia, CA).  The RNA was subjected to several quality control measures, including agarose gel electrophoresis to examine for RNA degradation, a spectrophotometer scan from 200 to 350 nm and capillary electrophoresis using an Agilent Bioanalyzer 2100 instrument.

Array hybridization/detection

RNA Labeling, hybridization and scanning were performed as recommended by Affymetrix in their GeneChip® expression Analysis Technical Manual (Affymetrix, Santa Clara, CA).  Fifteen micrograms of biotinylated cRNA was added to a total hybridization cocktail of 300 µl, and 200 µl was hybridized to each Affymetrix Human Genome HG133A GeneChip®.  Hybridization was at 45°C for 17 hours with constant rotation.  The hybridization mixture was then removed and the GeneChips® washed and doubly stained with phycoerythrin-labeled Streptavidin. GeneChips® were then scanned using the dedicated scanner, controlled by Affymetrix Microarray Suite version 5 (MAS5) software. The average intensity on each array was normalized by global scaling to a target intensity of 1000. Microarray Suite calculates a set of absolute metrics for each transcript: a measure of the expression level ("signal"), a detection call for each transcript: Present (P), Absent (A), or Marginal (M) and the level of confidence with which the sequence was detected.

Database and analysis

The data were exported from MAS5 and entered into a custom-designed database (MicroArray Data Portal) at the Center for Medical Genomics at the Indiana University School of Medicine. Data from genes that are not reliably detected in at least one experimental condition (detected on at least half of the individual arrays in at least one experimental condition) are filtered out before further analysis: this avoids calculations on data that primarily represent “noise” at or near background intensities3. Expression levels (signals) were log-transformed to make the data more normal before conducting t-tests; results of t-tests on the untransformed data are very similar, as are results of non-parametric statistical analyses (Mann-Whitney test).  In addition, hierarchical clustering was applied to data after filtering out genes that did not vary with the different conditions 4 by requiring that the ratio of standard deviation to mean across all of the arrays be equal to or greater than a specified level.

 

Quantification of mRNA expression levels using kinetic RT-PCR analysis

Kinetic RT-PCR was used to monitor expression of a subset of IFN inducible genes in IFN a treated PBMC.  Total RNA extracted from IFN treated PBMC was quantified using the RiboGreenŇ RNA Quantification kit (Molecular Probes, Eugene, OR).  The expression levels of selected IFN inducible genes based on the GeneChip data were determined using SYBRŇ Green I dye-based kinetic RT-PCR 5.  A 10 ul single-step RT-PCR reaction consists of 50 mM Bicine, 125 mM KOAc, pH 8.0, 8% glycerol, 3 mM Mn(OAc)2, 0.2 X SYBRŇ Green I diluted in DMSO, (Molecular Probes), 0.45 mM ROX (Sigma-Aldrich, St. Louis, MO), 200 mM dATP, 200 mM dGTP, 200 mM dCTP, 400 mM dUTP, 200 nM each primer, 0.2 units uracil N-glycosylase (Applied Biosystems, Foster City, CA), 1 unit rTth DNA polymerase (Applied Biosystems), and 2 ng total RNA from PBMC.  The samples were amplified at 50°C 2 min, 95°C 1 min, 60°C 30 min, followed by 95°C 30 sec, 60°C 30 sec for 50 cycles, held at 72°C using Applied Biosystems Prism 7900HT Sequence Detection System.  Each RNA sample was assayed for each target gene in triplicate together with a negative control.  Reactions with serially diluted run-off RNA transcripts (hTERT, human telomerase catalytic component gene) were included in each experiment as an external reference to monitor inter-experimental variations and to determine the “relative copy number” in each RNA sample.  Copy number is defined as a PCR signal generation unit.

The gene expression level in each sample was initially expressed as “relative copy numbers” determined by an external standard curve included in each PCR plate.  Then, the relative copy numbers were normalized by the relative gene expression levels of housekeeping genes.  A total of nine housekeeping genes (b2M, GAPDH, PBGD, PPP1CA, RNase P, U3, U8, U12 and U13) were assayed with other IFN inducible gene targets.  The final housekeeping genes (b2M, PBGD, PPP1CA, RNase P, U13, and U3) were chosen based on their consistence of the expression levels among all samples using geNorm software. (http://allserv.rug.ac.be-/~jvdesomp/genorm/index.html).  Finally, gene expression fold changes of IFN-a induction was determined by dividing the relative copy numbers of the same RNA sample after the treatment by the relative copy numbers of each RNA sample before the treatment.

 

RESULTS

Many genes were induced and down regulated by Peg-IFN-a, but essentially none were affected by ribavirin at the concentration used (Table 1). The number of genes with apparently altered expression in the presence of ribavirin (at 10 mg/ml, either with or without interferon) is less than that expected by random chance at each P value (Table 1). In contrast, PEG-IFN-a changes the expression of a greater number of genes than expected by chance, particularly at the most stringent P values (Table 1). The relative lack of effect of ribavirin is further demonstrated by hierarchical clustering of the data from the arrays, including in the analysis those genes that varied in expression across the experiment (selected as having a ratio of standard deviation to the mean ≥0.5) (Fig. 1). The array data from a given individual with and without ribavirin cluster together more closely than the arrays from another individual with either of those treatments.. The effects of interferon treatment on gene expression are large and consistent, whereas those of ribavirin are essentially undetectable. This allowed us to group the arrays on the basis of interferon treatment alone, giving a 10 x 10 array comparison that is much more powerful than a 5 x 5 comparison (Table 1). This merged analysis shows a very large number of genes whose expression is changed by interferon at very highly significant levels (supplemental data, also available at http://cmg.iupui.edu/pub /Taylor1    (upon publication of this article).

Genes induced or decreased by  IFN .

Because there was no detectable effect of ribavirin, we describe the results of the merged dataset, which represents genes whose expression was altered by interferon. Even using the stringent criterion of a significant difference from controls at the p ≤0.001 level, 541 genes were up-regulated by interferon (Supplementary data set 1). Of these 541 genes, 347 are unique characterized genes (i.e. appear in GeneCards and/or other databases), and 194 are unknown.

Likewise, at the same stringent criteria, 534 genes were down-regulated; of these, 354 were known genes (Supplementary data set 2).  The largest classes of genes induced, as a percentage of the total genes of that class on the array, were involved in defense/immunity proteins, cell death, transcriptional regulation, stress proteins and responses to external stimuli, including chemokines (Table 2). This is in general agreement with other reports on the classes of interferon stimulated genes 6-8, although our data analyze many more genes. The largest class of down-regulated genes are genes associated with metabolism, macromolecular biosynthesis, and transcriptional regulation.  To date there has been no detailed analysis of down regulated genes.

 Kinetic RT-PCR, is an accurate, sensitive and reliable method for quantitating mRNA levels in mixtures of total cellular RNA over a wide range of relative transcript abundance. A subset of the IFN inducible genes were selected for further kinetic RT-PCR analysis9. A comparison of the fold changes in expression as found by microarray analysis and kinetic RT-PCR is presented in Table 3.  There was good agreement between the data obtained from the microarrays and the data generated by kinetic RT-PCR, although some difference was observed in the magnitude of differential expression detected by the two methods. For example, OAS1 (12 fold vs. 24 fold), CD80 (2 fold vs. 10 fold), MX1 (8 fold vs. 38 fold), MX2 (6 fold vs. 24 fold), OAS3 (12 fold vs. 43 fold), and IFIT4 (12 fold vs. 82 fold). Because of its broad dynamic range, it is not surprising that kinetic RT-PCR detected larger fold changes than microarrays. Again, kinetic RT-PCR did not detect any gene expression changes in PBMC that have been treated by ribavirin alone. Overall, kinetic RT-PCR confirmed that the differential gene expression detected by microarrays indeed reflected the cellular mRNA levels in PBMC upon the treatment with PRG-IFN-a and ribavirin.

 

Novel interferon induced genes.

A large number of genes not previously identified as being induced by interferons were detected in this study (Supplementary data, Tables 1 )). Among these genes were ApoBec3a (20 fold), an RNA editing enzyme which has cytidine and deoxycytidylate deaminase activity10. The companion enzyme ADAR (adenosine deaminase) reported to be induced by IFNs 11was also induced (2 fold). Properdin, a key factor in the regulation of the complement alternative pathway12 was highly induced. We have found that this factor is also induced in cell lines by the combination of IFN-con1 and IFN-gamma (Ms in preparation). A number of transcription factors were induced including ATF3 (4.5 fold), an immediate response gene that is induced in cells exposed to various stress stimuli 13 and ATF4 (1.5 fold). Another presumptive transcription factor induced is HESX1 (20 fold); mutations in this gene affect the development of the pituitary gland14 .Induction of HESX1 is not unique to PBMC since we have found the HESX1 induction in a number of cell lines of non-hematopoietic origin (manuscript in preparation). The up-regulation of CD38 (6.7 fold) would indicate that interferon may play a role in the development of B-cells and B-cell maturation 15 . The Ly6E protein (8.4 fold) also induced is a cell surface protein expressed at high levels on activated peripheral T cells16.This complex is also activated by interferon, indicating an important role for interferon in both B cell and T-cell activation.  One of the genes most highly induced (132 fold), was sialoadhesion; this molecule is known to bind sialic acid molecules on the cell surface. Cig5 (Viperin) (18.7 fold), a protein first identified in HCMV infected and interferon treated cells 17 does not appear in earlier reports of interferon induced genes 6-8.

Cytokine and chemokine genes.

Since we initiated this study with a primary interest in the role of cytokines in the interferon response in hepatitis C patients 1,2, we examined cytokine expression levels in some detail. The induction pattern of the more common interleukins, chemokines and their receptors is presented in Table 4.  The only interleukins significantly induced were IL-1ra, IL-18, IL-15 and TNF-a. The receptors for IL-2, IL-15 and IL-12 were also up-regulated.

The most significantly suppressed cytokine mRNA's were those coding for IL-1a, IL1-b and IL-23. The following interleukins were not significantly induced or down regulated: IL-3, IL-6, IL-8, IL-10, IL-12, and IL-16.  IFN-g was not induced by Peg-IFN-a plus ribavirin in this study, as confirmed by kinetic RT-PCR. Likewise, no changes in expression of receptor genes were found for these interleukins. TNF-a was induced (1.7 fold change) at a marginally significant P value of 0.01. This is in agreement with previous reports from this laboratory 1 Similar results were obtained when PBMC were incubated with PEG-IFN-a alone. Among the chemokines induced were chemokines 1, 8, 10, 11, and 19, MCP-2 (SCYA8), and SCYB10 (IP-10) and among chemokines significantly down-regulated were chemokine ligand 5 (cytokine B5), and chemokines A 20, 22 and 24.

Genes involved in transcriptional regulation

As expected, STAT1 and STAT2 as well as Jak 2 were induced in PBMC following PEG-IFN-a treatment (Table 4).  Two regulatory genes related to the JAK/STAT pathway, NMI (n-myc and STAT interactor) and SOCS1 (suppressor of cytokine signaling), were also induced. These gene products regulate the STAT induction pathway, NMI in a positive fashion and SOCS1 as a negative regulator 18.  NMI protein interacts with all STATS except for STAT2 and has been reported to increase STAT mediated transcription in response to IL-2 and IFN- g.  SOCS1 binds to JAK kinases and negatively regulates the JAK signaling pathway 19 which has been reported to be induced by IL-3, EPO, CSF/CM-CSF and IFN-g.

 IFN-a treatment also results in the induction of DRAP1, IRF-2 and IRF-7.  DRAP-1 (DR1 associated protein) interacts with TATA binding protein (TBP) of TFIID and prevents the formation of an active complex, by enhancing DR-1 repression 20  IRF-2 is a competitive repressor of IRF-1, which is involved in the induction of Type I interferons as well as binding to the ISRE region of interferon inducible genes 21.  IRF-7 likewise binds to the ISRE and interferes with IRF-1 transcriptional activation.  IRF-7 is uniquely produced by hematopoietic cells 21

Genes involved in apoptosis

It has been suggested that the second stage of response to interferon treatment in hepatitis C patients is due to apoptosis of infected cells.  Thus we specifically examined those genes known to be associated with cell death (Table 4). TNFSF10 (TRAIL), a member of the TNF ligand superfamily that binds to the death signaling receptors DR4 and DR527 22, is induced 7-fold. . TNFRSF6, also known as APO-1, or FAS-1 receptor, was likewise elevated over 2-fold; TNFRSR6 contains a death domain adapter molecule and recruits caspase 8 to the activated receptor involved in the initiation of the caspase cascade 23.  RIPK2, a receptor interacting serine threonine kinase, interacts with CD40 or TNF receptor 24: its c-terminal region is also involved in caspase recruitment and activation. RIPK2 is induced nearly 2-fold. Thus the major pathway of apoptosis induced following PEG-IFN-a treatment of PBMC appears to be through the Fas/FAS ligand TRAIL system, and not through TNF-a (Figure 2). As expected, the expression of the interferon-inducible double-stranded RNA kinase (PRKR) was up-regulated approximately 3-fold by the PEG-IFN-a treatment .

Induction of known interferon-stimulated genes (ISGs) and anti-viral  proteins.

As expected, previously identified interferon related genes were induced (Table 2a,b and supplementary data).  These included genes known to be involved in the activation of the ISG gene family.  Although 7 or 8 interferon responsive factors (IRFs) have been identified, only IRF-1 (1.5 fold, p=.00056), IRF-2 (1.8 fold, p=0.003), IRF-4 (1.6, fold, p=0.003) and IRF-7 (4.0 fold, p=0.00001) were induced in PBMC.  Among other genes altered in expression were ISG-15, MX 1 and MX 2, and 2-5 Oligo-A synthetase isozymes.  The level of these genes is in agreement with those recently reported by Schlaak and co-workers 26

Discussion

In this paper we report the expression profile of genes induced in PBMC following 24 hours of treatment in vitro with PEG-IFN-a, ribavirin, and PEG-IFN-a plus ribavirin. Affymetrix GeneChips® allowed us to examine the expression of more than 22,000 human genes. To confirm the results from microarray analyses, we measured by kinetic RT-PCR 62 genes that were detected as induced in the microarray screen at a P <0.05, and found excellent agreement between the two methods (Table 3).

Ribavirin by itself had essentially no detectable effect on overall cellular gene expression.  IFN on the other hand, had a dramatic effect on global gene expression, inducing and down-regulating similar numbers of genes. We detected many more IFN-regulated genes than have previously been identified 6-8

In this study ribavirin (1-b-D-ribofuranosyl-1, 2, -triazole-3-carboxaminde) was used at what was considered physiological levels (10mg/ml). It is possible that at higher concentrations it would have greater effects in vitro. Ribavirin is a synthetic guanosine analogue with broad antiviral activities against DNA and RNA viruses 26. Although the molecular mechanism of ribavirin action in IFN/ribavirin combination therapy remains unclear, ribavirin is known to have no direct antiviral activities against HCV viral replication when it was used alone 27. Previous reports suggested that ribavirin acts as an immunomodulator and promotes T cell mediated immunity against HCV infection during IFN/ribavirin combination therapy 28,29. Ribavirin also acts as a  RNA mutagen in the HCV replicon system 30. It is possible that the induction of RNA editing enzymes such as apobec3a and ADAR will lead to an even greater mutation frequency leading to an “error catastrophe”. This is under investigation.

Since ribavirin had little effect either by itself or in the combination, we were able to merge the data ± ribavirin from 20 arrays into a 10 X 10 analysis in which the difference was presence or absence of PEG-IFN-a. We had sufficient samples to perform t-tests to give meaningful statistical and biological differences, and therefore did not have to resort to an arbitrary and non-biological cut off (e.g. 2 fold differences). We detected a total of 1061 non-redundant mRNA sequences either up regulated or down regulated following PEG-IFN-a treatment (supplementary material), many more interferon-regulated genes than have previously been identified 6-8, even when restricting our attention to genes that differed at P ≤ 0.001. The data we present were analyzed from matched experiments in which PBMC from an individual are divided and treated in parallel; data from preliminary experiments with samples from other individuals were essentially the same. It is possible that at the 24 hour time point studied some of IFN response reflect secondary events, although similar results have been found following shorter treatments of cell lines with the same IFNs (unpublished data).

We have compared our list of genes up regulated by IFN-a (supplementary material) with those previously published 6-8 as well as with the data base http:// www.lerner.ccf.org/labs/-williams. Almost all the genes identified in these earlier experiments appear in our analysis.  However, our data expand considerably the number of genes modulated by interferon. The largest percentage of genes induced by IFN-a involved cell death, defense and immunity proteins, stress response, signaling, and transcriptional regulation (Table 2).  A number of novel genes were identified in this study that may be important in the interferon response. These include the cytidine and deoxycytidine deaminase proposed to be an editing enzyme, and a large group of transcription factors. ATF4 is activated by phosphorylation of eIF2, and thus may play a major role in the regulation of amino acids and other metabolites 31. Phosphorylation of eIF2 is also a result of PKR activity. Thus these genes may be co-regulated and related to the anti-viral or apoptotic response. An homeobox protein 14 of unknown function, but that has been detected in other cell lines treated with interferon (in preparation), and viperin 17, a previously identified but uncharacterized protein that has inhibitory effects on human cytomegalovirus, were identified. Properdin, a key element of the complement alternative cascade is also induced by Peg-IFN-a.  This was rather surprising since it has been reported that properdin activity is suppressed by IFN-g 12. A possible role for interferons in the induction of the complement cascade has never been studied before and is now under investigation.

There is no published list of genes down regulated by IFN-a isoforms, so this report greatly expands our knowledge of gene suppression by IFNs. Treatment of PBMC with PEG-IFN-a results in a down regulation of overall metabolism and translational regulation, which may reflect the induction of apoptotic related genes (Table 4). A large number of mRNAs encoding ribosomal proteins are  reduced in concentration (supplemental data). If this decrease of mRNA was due to global mRNA degradation, it would be a general phenomenon and not confined to a select number of genes.

Interestingly, we were unable to detect the induction of IFN-g mRNA, although a large number of genes previously reported to be IFN-g inducible were detected. This is in agreement with our previous results from an analysis of serum samples from HCV patients treated with the consensus IFN, in which we were unable to detect increases in IFN-g or most other cytokines 1,2 This lack of IFN-g induction is in agreement with the work of Schlaak and coworkers25. Kinetic RT-PCR confirmed that either very low or non-detectable amounts of IFN-g were present in PBMC treated by PEG- IFN-a, and that the induced genes were likely due the effects of PEG-IFN-a instead of secondary induction.

We were particularly interested in cytokines induced by the combination drug treatment, since previous work from this lab had detected little cytokine activity in serum samples from hepatitis C patients treated with IFN-con1 1,2. Table 4 presents a list of cytokines and chemokines altered at the mRNA level by this treatment in vitro. One of the cytokines induced by in this study was IL-18, which was originally described as an IFN-g inducing factor (GIF) in mouse spleen cells32; IL-18 has not been previously shown to be induced by type I interferons.  An important function of IL18 is the regulation of functionally distinct subsets of T-helper cells required for cell-mediated immune responses 33  IL-18 also functions as a growth and differentiation factor for Th1 cells, and up regulates Fas ligand mediated cytotoxic activity of murine natural killer cells34 , probably through the induction of IFN-g. IL-18 may have additional roles other than the induction of IFN-g, and in PBMC this may not be its predominant role. 

Il-15, a recently discovered cytokine with T-cell stimulating activity similar to IL-2 35,36 was also induced in this study.  IL-15 is activated in monocyte/macrophages 37.  The IL-15 receptor and IL-2 receptors are both induced by PEG-IFN-a (Table 4). The high affinity receptor for IL-15 involves a complex with the IL-2 receptor 38  Thus, it was of interest that both the IL-15 receptor and IL-2 receptor (but not IL-2) are both up regulated following treatment, suggesting that IL-15 may be the major activator of T-cells following interferon treatment.

In a previous study 39, IFN-a therapy was associated with a reduction in levels of the T-helper type 2 (Th2) cytokines IL-4 and IL-10. Production of IL-1b and TNF-a by peripheral blood mononuclear cells also was found to decrease during IFN-a therapy 40  Data from our analysis confirms that the pro-inflammatory cytokines IL-1a and IL-1b and their receptors are coordinately suppressed by PEG-IFN-a, whereas TNF-a appeared to increase, although at a low level.

Apoptosis, programmed cell death, provides a mechanism for controlling the number and types of active blood cells, as well as for the elimination of viral infected cells. A large number of genes on the apoptotic pathway were induced by PEG-IFN-a  treatment. In mammalian cells, one pathway of activating the caspases is through the activation of receptors by members of the tumor necrosis family. One of the best-characterized receptors of this family is FAS (Table 4; TNFRSF-6), also known as APT-1/CD95 (apo-1) (fig. 2).  This receptor is highly induced by PEG-IFN-a, as is its ligand TNSF10 (TRAIL).  Fas and TRAIL are induced by IFN-a in PBMC of HIV patients 41.  We propose that the binding of TRAIL to FAS results in the synthesis and activation of caspase 1 (ICE-1), caspase 7 and caspase 9. Other genes involved in the regulation or induction of apoptosis also include Bcl-G, a new member of the Bcl-2 family 42.  Over-production of Bcl-G in cells induced apoptosis 43  Both RIPK1 and RIPK2 (table 4) are transducers and integration signals for the immune system 24.  These serine threonine kinase associated receptors are part of the TNF receptor complex and are implicated in activation of NF-kappa B and cell death. TSSC3 (Table 4) is the human homologue of the mouse apoptosis gene TDAG5144.

In conclusion, a large number of genes are induced by the in vitro treatment of PBMC with PEG-IFN-a.  Our list expands considerably the number of genes previously reported to be IFN-a induced, and indicates that PEG-IFN-a also suppresses a large number of genes, particularly those related to overall biosynthesis and metabolism in the cell. Many of these may be secondary effects of primary gene induction. We have also demonstrated that ribavirin, used clinically in combination with PEG-IFN-a, has little effect upon steady-state mRNA levels, and therefore must function by another mechanism. Few interleukins are induced by PEG-IFN-a, although genes involved with cell motility, such as chemokines, are induced.  The finding that PEG-IFN-a also induces large numbers of genes involved in cell death and regulation of apoptosis gives credence to the fact that PEG-IFN-a is not only an antiviral agent but is intrinsically involved in cell regulation and may act as a tumor suppressor

 

Acknowledgements

This work was supported by a grant from the US National Institutes of Health, NIDDK DK60309 (MWT) and a pilot grant from Schering-Plough (MWT). The microarray studies were carried out using the facilities of the Center for Medical Genomics at Indiana University School of Medicine. The Center for Medical Genomics is supported in part by grants from the Indiana 21st Century Research and Technology Fund and the Indiana Genomics Initiative (supported in part by the Lilly Endowment, Inc.).

Competing interests statement:

The authors declare that they have no competing financial interests.

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TABLES

 

Table 1. Number of genes modulated by PEG-IFN-a and ribavirin and the combination at different P values.

 

Table 2. Classes of genes induced or down regulated by Peg-IFN-a

 

Table 3. Comparison  of micro-array levels and kinetic real time PCR of genes modulated by Peg-IFN-a

 

Table 4. Induction or down regulation of specific classes of genes related to cytokines, chemokines, transcription factors, inflammation and apoptosis.

 

 

 

Figures

 

 

Figure 1. Two way hierarchical clustering (using CLUSFLAVOR 6.0) shows that there is a major difference in overall gene expression between samples treated with or without interferon, but that samples from the same blood draw (indicated by common first and last character; middle character indicates treatment group, with 2 = no treatment, 3 = PEG-IFN, 4 = ribavirin, 5 = PEG-IFN + Ribavirin) cluster together whether or not treated with ribavirin (e.g. D41 and D21 without interferon, D31 and D51 with interferon). The region shown was selected from the full dataset because it shows several interferon induced genes (labeled at right), and demonstrates clear differences in their pattern of expression

 

Figure 2 . Apoptotic pathway. Genes inside squares are induced by PEG-IFN-a

 

 

Table 1. Number of genes modulated by PEG-IFN-a and ribavirin and the combination at different P values.

 

 

Random Probability†

No drug vs. Ribavirin

No drug vs. Interferon

IFN vs IFN + Ribavirin

No drug vs combined treatment.

Arrays compared

 

5 x 5

5 x 5

5 x 5

10 x 10

Genes detected*

10,709

10,637

10,823

10,745

10,709

P ≤ 0.05

535

254

1,437

478

3,372

P ≤ 0.01

107

48

546

85

2,043

P ≤ 0.001

10

3

162

2

1,061

P ≤ 0.0001

1

0

52

0

563

 

 

 

 

 

 

*Present in at least half of the arrays in at least one experimental condition

†Number of genes expected to meet the criterion by chance, based on the normal distribution.

#The increase in numbers is not due to an effect of the drug combination, but rather to the great increase in statistical power due to the larger number of arrays compared.

 

 

Table 2. Classes of genes induced or down regulated by Peg-IFN-a

 

 

Gene Ontology

# on array

Induced

% 

Repressed

% 

Total changed

%

Ontology total (Database)

8627

780

9.0%

863

10.0%

1643

19.0%

apoptosis regulator

25

3

12.0%

1

4.0%

4

16.0%

biosynthesis

184

8

4.3%

61

33.2%

69

37.5%

carbohydrate metabolism

65

5

7.7%

10

15.4%

15

23.1%

catabolism

120

11

9.2%

11

9.2%

22

18.3%

cell cycle

153

6

3.9%

6

3.9%

12

7.8%

cell death

147

31

21.1%

7

4.8%

38

25.9%

Cell motlity

94

14

14.9%

11

11.7%

25

26.6%

cell organization and biogenesis

119

6

5.0%

7

5.9%

13

10.9%

cell proliferation

129

8

6.2%

11

8.5%

19

14.7%

cell shape and cell size control

68

5

7.4%

5

7.4%

10

14.7%

cell surface linked signal transduction

177

21

11.9%

13

7.3%

34

19.2%

cell-cell signaling

115

14

12.2%

7

6.1%

21

18.3%

defense/immunity protein

47

10

21.3%

2

4.3%

12

25.5%

enzyme regulators

130

14

10.8%

4

3.1%

18

13.8%

enzymes

1210

68

5.6%

66

5.5%

134

11.1%

Intracellular signaling cascade

187

20

10.7%

11

5.9%

31

16.6%

ligand binding

1184

107

9.0%

140

11.8%

247

20.9%

nucleic acid metabolism

489

19

3.9%

19

3.9%

38

7.8%

protein biosynthesis

184

4

2.2%

59

32.1%

63

34.2%

protein degradation

82

9

11.0%

8

9.8%

17

20.7%

protein modification

209

11

5.3%

9

4.3%

20

9.6%

protein targeting

53

2

3.8%

4

7.5%

6

11.3%

response to external stimulus

400

72

18.0%

41

10.3%

113

28.3%

signal transducers

492

48

9.8%

43

8.7%

91

18.5%

stress reponse

296

42

14.2%

27

9.1%

69

23.3%

transcription regulator

193

35

18.1%

19

9.8%

54

28.0%

translation regulators

44

0

0.0%

8

18.2%

8

18.2%

transport

326

14

4.3%

21

6.4%

35

10.7%

Total

6922

607

8.8%

631

9.1%

1238

17.9%

 

 

Table 3. Comparison  of micro-array levels and kinetic real time PCR of genes modulated by Peg-IFN-a

 

 

 

GeneSymbol

GenBank Acc. No.

Microarrays1

RTQPCR2

 

GeneSymbol

GenBank Acc. No.

Microarrays1

RTQPCR2

ADAR

NM_001111.2

1.9

2.7

 

IRF1

NM_002198.1

1.5

1.9

AIM1

U83115.1

1.2

0.3

 

IRF2

NM_002199.2

2.1

1.7

AIM2

NM_004833.1

1.8

4.6

 

IRF4

NM_002460.1

1.7

1.8

ATF3

NM_001674.1

4.5

9.3

 

ISG20

U88964

4.7

9.7

BAG1

NM_004323.2

1.7

2.3

 

ISGF3G

NM_006084.1

1.6

1.6

BCL2

NM_000633.1

1.3

1.7

 

JAK2

NM_004972.2

2.7

4.0

BST2

NM_004335.2

4.1

4.0

 

LOC55893

NM_018660.1

0.8

10.0

CASP1

AI719655

2.1

2.3

 

MMP9

NM_004994.1

0.4

0.3

CASP3

NM_004346.1

1.2

2.5

 

MNDA

NM_002432.1

6.2

6.2

CCR2

NM_000647.2

0.6

0.3

 

MT2A

NM_005953.1

1.8

10.6

CD80

NM_005191.1

2.4

9.4

 

MX1

NM_002462.1

7.3

37.4

EEF1A1

NM_001402.1

0.8

0.7

 

MX2

NM_002463.1

5.7

22.9

EIF2B4

AF112207.1

0.8

0.6

 

NFKB1

M55643.1

1.3

1.3

EIF2S1

NM_004094.1

1.2

0.8

 

NMI

NM_004688.1

2.8

2.4

G1P3

NM_022873.1

4.4

27.7

 

OAS1

NM_016816.1

11.7

23.2

GAPDH

NULL

0.6

0.5

 

OAS2

NM_016817.1

5.1

10.9

GBP1

BC002666.1

3.9

6.3

 

OAS3

NM_006187.1

11.9

42.9

GBP2

NM_004120.2

1.6

2.6

 

PLSCR1

NM_021105.1

3.2

3.1

GCH1

NM_000161.1

3.0

4.0

 

PML

NM_002675.1

3.9

4.9

HIF1A

NM_001530.1

0.8

0.7

 

PRKR

NM_002759.1

3.3

8.7

HLA-C

U62824.1

1.4

1.9

 

PRKRIR

AF081567.1

0.8

0.9

ICSBP1

AI073984

1.4

1.0

 

PSMB8

U17496.1

2.0

0.4

IFI16

NM_005531.1

2.3

3.0

 

PSMB9

NM_002800.1

2.1

2.1

IFI27

NM_005532.1

36.8

356.1

 

RELA

M62399.1

1.3

1.5

IFI35

BC001356.1

5.6

6.1

 

SP110

NM_004509.1

2.4

3.0

IFIT4

NM_001549.1

82.2

11.7

 

SSA1

NM_003141.1

2.0

3.1

IFITM2

NM_006435.1

2.8

6.2

 

STAT1

NM_007315.1

2.2

3.6

IL12RB2

NM_001559.1

2.1

2.9

 

STAT2

NM_005419.1

2.8

4.4

IL15

NM_000585.1

2.1

2.5

 

TIMP1

NM_003254.1

0.2

0.4

IL16

NM_004513.1

0.9

1.1

 

TNFSF10

U57059.1

9.0

14.3

IL1RN

AW083357

6.8

17.1

 

TRIM22

AA083478

2.7

5.3

IL8

NM_000584.1

0.7

0.8

 

TUBB2

BC004188.1

1.1

1.0

INDO

M34455.1

4.5

9.3

 

WARS

M61715.1

2.3

3.0

 

 

 

 

 

 

 

 

 

1PValue≤ 0.05

 

 

 

 

 

 

 

 

2Real-Time RT-PCR

 

 

 

 

 

 

 

 

 

 

Table 4. Induction or down regulation of specific classes of genes related to cytokines, chemokines, transcription factors, inflammation and apoptosis.

 

 

 

Gene

Fold Change

P-value

Description

Gene Family

 

 

 

 

Interleukins

Induced

 

 

 

 

IL-1Ra

7.5

<0.0001

interleukin 1 receptor antagonist

 

IL-1 member 9

3.3

0.02

interleukin 1-related protein 2

 

IL-18

3

0.0018

interleukin 18 (interferon-gamma-inducing factor)

 

IL-15

1.98

<0.0001

interleukin 15

 

TNF-a

1.69

0.01

tumor necrosis factor alpha

 

Suppressed

 

 

 

 

Il-1a

-4.11

0.008

interleukin 1 alpha

 

IL-1b

-2.1

0.02

interleukin 1 beta

 

IL-23

-1.69

0.0007

interleukin 23, alpha subunit p19

 

Induced

 

 

 

Interleukin Receptors

IL-15

3.22

<0.0001

interleukin 15 receptor

 

IL-2

2.26

0.0001

interleukin 2 receptor

 

IL-12

2.2

0.0001

interleukin 12 receptor

 

Suppressed

 

 

 

 

IL-13RA

-1.54

0.0036

interleukin 13 receptor alpha

 

IL-17R

-1.49

0.003

interleukin 17 receptor

 

IL-21R

-1.64

0.0008

interleukin 21 receptor

 

IL-4R

-1.42

0.0002

interleukin 4 receptor

 

IL-1R

-1.92

0.0007

interleukin 1 receptor

 

Induced

 

 

 

 

CXCL11

48.37

0.003

chemokine (C-X-C motif) ligand 11

Chemokines

CXCL10

8.76

0.0002

chemokine (C-X-C motif) ligand 10

 

CCL8

5.1

<0.0001

chemokine (C-C motif) ligand 8

 

CCL19

2.56

0.002

chemokine (C-C motif) ligand 19

 

XCL1

1.33

0.011

chemokine (C motif) ligand 1

 

Suppressed

 

 

 

 

CKLF1

-1.52

0.009

chemokine-like factor 1

 

CCL22

-1.69

0.0006

chemokine (C-C motif) ligand 22

 

CCL20

-2.58

0.0177

chemokine (C-C motif) ligand 20

 

CCL24

-2.72

0.0024

chemokine (C-C motif) ligand 24

 

CXCL1

-2.89

0.0046

chemokine (C-X-C motif) ligand 1

 

CXCL5

-4.58

0.0054

chemokine (C-X-C motif) ligand 5

Chemokine Receptors

Induced

 

 

 

 

CMKLR1

1.79

0.0038

chemokine-like receptor 1

 

CCR1

1.77

0.0007

chemokine (C-C motif) receptor 1

 

CCR5

1.5

0.002

chemokine (C-C motif) receptor 5

Pathways

 

 

 

 

Transcription Regulation

Induced

 

 

 

 

PML

4.35

4E-05

promyelocytic leukemia

 

ATF3

4.2

0.0001

activating transcription factor 3

 

IFI35

3.48

2E-05

interferon-induced protein 35

 

STAT2

3.4

9E-05

Stat2 type a

 

TFEC

3.17

0.0016

transcription factor EC

 

IRF7

2.95

2E-05

interferon regulatory factor 7

 

PRKR

2.95

1E-05

protein kinase,IFN-inducible double stranded RNA dependent

 

STAT1

2.46

0.0002

signal transducer and activator of transcription 1, 91kDa

 

ZNF147

2.23

2E-05

zinc finger protein 147 (estrogen-responsive finger protein)

 

STAT2

2.2

0.0002

signal transducer and activator of transcription 2, 113kDa

 

SP100

2.13

1E-05

nuclear antigen Sp100

 

NMI

2.11

5E-05

N-myc (and STAT) interactor

 

TRIM22

2.02

2E-05

tripartite motif-containing 22

 

NFE2L3

1.93

0.0012

nuclear factor (erythroid-derived 2)-like 3

 

KLF5

1.87

0.0005

Kruppel-like factor 5 (intestinal)

 

HIRA

1.83

0.0024

HIR histone cell cycle regulation defective homolog A (S.cerevisiae)

 

TEL2

1.79

0.0003

transcription factor ets

 

IRF2

1.74

0.0046

interferon regulatory factor 2

 

TARBP1

1.69

0.0046

TAR (HIV) RNA binding protein 1

 

CREG

1.6

0.0047

cellular repressor of E1A-stimulated genes

 

SP140

1.6

0.0002

SP140 nuclear body protein

 

IRF4

1.58

0.004

interferon regulatory factor 4

 

SUPT3H

1.57

0.0002

Transcription factor SUPT3H (SUPT3H) mRNA, complete cds

 

DRAP1

1.56

2E-05

DR1-associated protein 1 (negative cofactor 2 alpha)

 

ELF1

1.55

7E-05

E74-like factor 1 (ets domain transcription factor)

 

TCF4

1.55

0.0011

transcription factor 4

Apoptosis

Induced

 

 

 

 

TNFSF10

7.17

0.0001

tumor necrosis factor (ligand) superfamily, member 10

 

CD38

5.25

0.0007

CD38 antigen (p45)

 

MX1

4.08

1E-05

myxovirus (influenza virus) resistance 1, IFN-inducible protein p78

 

BCLG

3.8

6E-05

apoptosis regulator BCL-G

 

PRKR

2.95

1E-05

protein kinase, IFN-inducible double stranded RNA dependent

 

TNFRSF6

2.29

0.0004

tumor necrosis factor receptor superfamily, member 6

 

CASP1

1.97

3E-05

caspase 1, apoptosis-related cysteine protease

 

CASP10

1.88

0.0003

caspase 10, apoptosis-related cysteine protease

 

RIPK2

1.86

0.0004

receptor-interacting serine-threonine kinase 2

 

TSSC3

1.81

0.0002

tumor suppressing subtransferable candidate 3

 

CFLAR

1.74

5E-05

CASP8 and FADD-like apoptosis regulator

 

RIPK1

1.72

1E-05

receptor (TNFRSF)-interacting serine-threonine kinase 1

 

BAG1

1.64

0.0004

BCL2-associated athanogene

 

CASP7

1.55

0.0003

caspase 7, apoptosis-related cysteine protease

 

TIA1

1.55

0.0006

TIA1 cytotoxic granule-associated RNA binding protein

 

GADD45B

1.55

0.0009

growth arrest and DNA-damage-inducible, beta

 

TNFRSF9

1.52

0.0031

tumor necrosis factor receptor superfamily, member 9

 

CUL1

1.51

0.007

cullin 1

 

Suppressed

 

 

 

 

DEFCAP

-1.53

0.0001

death effector filament-forming Ced-4-like apoptosis protein

 

LGALS1

-1.65

0.0024

lectin, galactoside-binding, soluble, 1 (galectin 1)

 

CD14

-2.7

3E-05

CD14 antigen

Inflammatory Response

Induced

 

 

 

 

CXCL10

8.76

0.0002

chemokine (C-X-C motif) ligand 10

 

IL1RN

5.96

2E-05

interleukin 1 receptor antagonist

 

CCL8

5.1

1E-05

chemokine (C-C motif) ligand 8

 

NMI

2.42

<0.00001

N-myc (and STAT) interactor

 

APOL3

2.16

8E-05

apolipoprotein L, 3

 

RIPK2

2.04

1E-05

receptor-interacting serine-threonine kinase 2

 

CCR1

1.77

0.0007

chemokine (C-C motif) receptor 1

 

BLNK

1.63

0.001

B-cell linker

 

Suppressed

 

 

 

 

CCL22

-1.69

0.0007

chemokine (C-C motif) ligand 22

 

IL1R1

-1.92

0.0007

interleukin 1 receptor, type I

 

LTA4H

-2.56

0.0001

leukotriene A4 hydrolase

 

S100A8

-2.61

1E-05

S100 calcium binding protein A8 (calgranulin A)

 

PROCR

-2.72

0.0005

protein C receptor, endothelial (EPCR)

 

S100A9

-3.23

<0.00001

S100 calcium binding protein A9 (calgranulin B)

 

S100A12

-3.74

1E-05

S100 calcium binding protein A12 (calgranulin C)

 

CD14

-4.15

<0.00001

CD14 antigen

 

FPR1

-4.34

0.0008

formyl peptide receptor 1

 

 

 

 

 

 

 
 

 

Figures

Figure 1. Two way hierarchical clustering (using CLUSFLAVOR 6.0) shows that there is a major difference in overall gene expression between samples treated with or without interferon, but that samples from the same blood draw (indicated by common first and last character; middle character indicates treatment group, with 2 = no treatment, 3 = PEG-IFN, 4 = ribavirin, 5 = PEG-IFN + Ribavirin) cluster together whether or not treated with ribavirin (e.g. D41 and D21 without interferon, D31 and D51 with interferon). The region shown was selected from the full dataset because it shows several interferon induced genes (labeled at right), and demonstrates clear differences in their pattern of expression

 

Figure 2 . Apoptotic pathway. Genes inside squares are induced by PEG-IFN-a.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Supplementary table 1 ( up-regulated genes)

 

GeneSymbol

Genbank

Fold Change

Description

ACK1

NM_005781.2

1.68

activated p21cdc42Hs kinase

ADAM19

Y13786.2

1.95

a disintegrin and metalloproteinase domain 19

ADAMDEC1

NM_014479.1

2.18

ADAM-like, decysin 1

ADAR

NM_001111.2

1.91

adenosine deaminase, RNA-specific

ADPRTL3

AF083068.1

1.68

ADP-ribosyltransferase

AGRN

AI424797

1.84

agrin

AIM2

NM_004833.1

1.8

absent in melanoma 2

AKAP2

NM_007203.1

2.15

A kinase (PRKA) anchor protein 2

ANKHZN

NM_016376.1

2.05

ANKHZN protein

APOBEC3A

U03891.2

19.16

apolipoprotein B mRNA editing enzyme,

APOL1

AF323540.1

2.97

apolipoprotein L, 1

APOL3

NM_014349.1

2.18

apolipoprotein L, 3

APOL6

NM_030641.1

3.18

apolipoprotein L, 6

ARHGAP8

AA533284

1.5

Rho GTPase activating protein 8

ARHGEF11

NM_014784.1

1.67

Rho guanine nucleotide exchange factor (GEF) 11

ARHGEF3

NM_019555.1

1.77

Rho guanine nucleotide exchange factor (GEF) 3

ATF3

NM_001674.1

4.53

activating transcription factor 3

ATF4

NM_001675.1

1.31

activating transcription factor 4 (tax-responsive enhancer element B67)

ATOX1

NM_004045.1

1.68

ATX1 antioxidant protein 1 homolog (yeast)

ATP10A

N35112

2.68

ATPase, Class V, type 10A

B4GALT5

BF691447

2.06

UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 5

BAG1

AF116273.1

1.89

BCL2-associated athanogene

BAZ1A

NM_013448.1

1.65

bromodomain adjacent to zinc finger domain, 1A

BCLG

NM_030766.1

4.17

apoptosis regulator BCL-G

BCRP1

AV755522

3.82

clone IMAGE:4074138, mRNA, mRNA sequence

BF

NM_001710.1

7.85

B-factor, properdin

BLNK

NM_013314.1

1.88

B-cell linker

BLVRA

AA740186

2.78

biliverdin reductase A

BRD2

D42040.1

1.42

bromodomain containing 2

BRDG1

NM_012108.1

2.29

BCR downstream signaling 1

BST2

NM_004335.2

4.09

bone marrow stromal cell antigen 2

BTN2A1

NM_007049.1

1.41

butyrophilin, subfamily 2, member A1

BTN3A1

NM_007048.1

1.58

butyrophilin, subfamily 3, member A1

BTN3A3

NM_006994.2

1.61

butyrophilin, subfamily 3, member A3

C12orf6

NM_020367.1

2.19

chromosome 12 open reading frame 6

C14orf3

NM_012111.1

1.26

chromosome 14 open reading frame 3

C1GALT1

NM_020156.1

1.73

core 1 UDP-galactose:N-acetylgalactosamine-alpha-R beta 1,3-galactosyltransferase

C1orf28

NM_024529.1

1.74

chromosome 1 open reading frame 28

C1orf29

NM_006820.1

4.72

chromosome 1 open reading frame 29

C20orf18

BE788439

1.78

chromosome 20 open reading frame 18

C4S-2

NM_018641.1

2.63

chondroitin 4-O-sulfotransferase 2

C6orf37

AW246673

3.77

chromosome 6 open reading frame 37

C7orf14

AW008531

1.46

chromosome 7 open reading frame 14

CACNA1A

AA769818

2.78

calcium channel, voltage-dependent, P/Q type, alpha 1A subunit

CAPN2

M23254.1

1.56

calpain 2, (m/II) large subunit

CASP1

U13699.1

2.42

caspase 1, apoptosis-related cysteine protease

CASP10

NM_001230.1

2.18

caspase 10, apoptosis-related cysteine protease

CASP4

AL050391.1

1.55

caspase 4, apoptosis-related cysteine protease

CASP7

NM_001227.1

1.61

caspase 7, apoptosis-related cysteine protease

CAST

AF327443.1

1.59

calpastatin

CBR1

BC002511.1

2.45

carbonyl reductase 1

CCL8

AI984980

14.49

chemokine (C-C motif) ligand 8

CCND3

NM_001760.1

1.36

cyclin D3

CCR1

AI421071

2.01

chemokine (C-C motif) receptor 1

CCR5

NM_000579.1

1.57

chemokine (C-C motif) receptor 5

CD164

AF263279.1

2

CD164 antigen, sialomucin

CD2AP

NM_012120.1

2.28

CD2-associated protein

CD38

NM_001775.1

6.69

CD38 antigen (p45)

CD47

BG230614

1.27

CD47 antigen (integrin-associated signal transducer)

CD69

L07555.1

1.81

CD69 antigen (p60, early T-cell activation antigen)

CD80

NM_005191.1

2.42

CD80 antigen (CD28 antigen ligand 1, B7-1 antigen)

CD83

NM_004233.1

2.03

CD83 antigen

CEB1

NM_016323.1

9.6

cyclin-E binding protein 1

CECR1

NM_017424.1

2.1

cat eye syndrome chromosome region

CENTD1

AB011152.1

1.41

centaurin, delta 1

CFLAR

AF041461.1

1.79

CASP8 and FADD-like apoptosis regulator

CHSY1

NM_014918.1

1.43

carbohydrate (chondroitin) synthase 1

cig5

AI337069

18.65

vipirin

CKS1B

NM_001826.1

1.37

CDC28 protein kinase regulatory subunit 1B

CMT2

NM_014628.1

1.33

gene predicted from cDNA with a complete coding sequence

CNP

BC001362.1

1.75

2`,3`-cyclic nucleotide 3` phosphodiesterase

COPEB

BE675435

2.16

core promoter element binding protein

COX17

NM_005694.1

1.42

COX17 homolog, cytochrome c oxidase assembly protein (yeast)

CRACC

NM_021181.2

3.98

19A24 protein

CREG

NM_003851.1

1.78

cellular repressor of E1A-stimulated genes

CRFG

NM_012341.1

1.33

G protein-binding protein CRFG

CRSP6

AF105421.1

1.36

cofactor required for Sp1 transcriptional activation, subunit 6,

CXCL10

NM_001565.1

30.6

chemokine (C-X-C motif) ligand 10

CXCL11

AF002985.1

56.27

chemokine (C-X-C motif) ligand 11

CXCL9

NM_002416.1

2.93

chemokine (C-X-C motif) ligand 9

CYCS

BC005299.1

1.29

cytochrome c, somatic

D13S106E

NM_005800.1

1.33

highly charged protein

DAPP1

NM_014395.1

1.66

dual adaptor of phosphotyrosine and 3-phosphoinositides

DC13

NM_020188.1

1.37

DC13 protein

DCK

NM_000788.1

1.74

deoxycytidine kinase

DDX1

NM_004939.1

1.21

DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 1

DEFB1

U73945.1

1.82

defensin, beta 1

DISC1

NM_018662.1

1.61

disrupted in schizophrenia 1

DNMT1

NM_001379.1

1.31

DNA (cytosine-5-)-methyltransferase 1

DNPEP

NM_012100.1

1.44

aspartyl aminopeptidase

DRAP1

NM_006442.1

1.72

DR1-associated protein 1 (negative cofactor 2 alpha)

DUSP5

U16996.1

2.69

dual specificity phosphatase 5

E2-EPF

NM_014501.1

1.62

ubiquitin carrier protein

ECE1

BF969352

1.82

clone IMAGE:4845226, mRNA, mRNA sequence

ECGF1

AW613387

2.02

endothelial cell growth factor 1 (platelet-derived)

ELF1

AL559590

1.53

E74-like factor 1 (ets domain transcription factor)

ENPP2

L35594.1

2.68

ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)

FBXO7

NM_012179.1

1.21

F-box only protein 7

FEM1C

AI862658

1.44

fem-1 homolog c (C.elegans)

FLN29

NM_006700.1

5.53

FLN29 gene product

FMR1

AI743037

1.58

fragile X mental retardation 1

FUT4

AF305083.1

2.03

fucosyltransferase 4 (alpha (1,3)

G1P2

NM_005101.1

9.86

interferon, alpha-inducible protein (clone IFI-15K)

GIP3

NM_022873.1

4.36

interferon, alpha-inducible protein (clone IFI-6-16)

GADD45B

AF078077.1

1.67

growth arrest and DNA-damage-inducible, beta

GBP1

NM_002053.1

4.43

guanylate binding protein 1, interferon-inducible, 67kDa

GBP2

NM_004120.2

1.62

guanylate binding protein 2, interferon-inducible

GCH1

NM_000161.1

3.03

GTP cyclohydrolase 1 (dopa-responsive dystonia)

GG2-1

BC005352.1

1.63

TNF-induced protein

GLS

AF097493.1

1.47

glutaminase

GNG5

NM_005274.1

1.4

guanine nucleotide binding protein (G protein), gamma 5

GPR43

NM_005306.1

4.7

G protein-coupled receptor 43

GRP3

NM_015376.1

3.36

guanine nucleotide exchange factor for Rap1

GTF2B

NM_001514.2

1.46

general transcription factor IIB

GTPBP1

NM_004286.1

1.5

GTP binding protein 1

GTPBP2

NM_019096.1

2.09

GTP binding protein 2

H2AFO

NM_003516.1

1.85

H2A histone family, member O

H3F3B

NM_005324.1

1.31

H3 histone, family 3B (H3.3B)

HCC8

NM_016516.1

1.41

tumor antigen SLP-8p

HDAC9

NM_014707.1

1.97

histone deacetylase 9

HESX1

U82811.1

18.71

homeo box (expressed in ES cells) 1

HIMAP4

NM_018326.1

1.77

immunity associated protein 4

HLA-B

L07950.1

1.2

major histocompatibility complex, class I, B

HLA-C

U62824.1

1.43

major histocompatibility complex, class I, C

HLA-DPA1

M27487.1

1.81

major histocompatibility complex, class II, DP alpha 1

HLA-DQA1

BG397856

2.09

major histocompatibility complex, class II, DQ alpha 1

HLA-E

M31183.1

1.58

major histocompatibility complex, class I, E

HLA-F

NM_018950.1

1.35

major histocompatibility complex, class I, F

HLA-G

M90684.1

1.37

HLA-G histocompatibility antigen, class I, G

HNRPF

AI591354

1.53

heterogeneous nuclear ribonucleoprotein F

HSPA1A

NM_005345.3

1.82

heat shock 70kDa protein 1A

HSPA8

AF352832.1

1.38

heat shock 70kDa protein 8

HSPB1

NM_001540.2

1.96

heat shock 27kDa protein 1

HSPCA

BG420237

1.38

heat shock 90kDa protein 1, alpha

HSXIAPAF1

NM_017523.1

3.95

XIAP associated factor-1

IDH3A

AI826060

2.37

isocitrate dehydrogenase 3 (NAD+) alpha

IFI16

BG256677

2.53

interferon, gamma-inducible protein 16

IFI27

NM_005532.1

36.85

interferon, alpha-inducible protein 27

IFI35

BC001356.1

5.63

interferon-induced protein 35

IFI44

BE049439

7.91

interferon-induced protein 44

IFIT1

NM_001548.1

19.51

interferon-induced protein with tetratricopeptide repeats 1

IFIT2

BE888744

15.37

interferon-induced protein with tetratricopeptide repeats 2

IFIT4

NM_001549.1

11.69

interferon-induced protein with tetratricopeptide repeats 4

IFITM2

NM_006435.1

2.81

interferon induced transmembrane protein 2 (1-8D)

IFITM3

BF338947

3.38

interferon induced transmembrane protein 3 (1-8U)

IFRG28

NM_022147.1

5.45

28kD interferon responsive protein

IL15

NM_000585.1

2.13

interleukin 15

IL15RA

NM_002189.1

3.46

interleukin 15 receptor, alpha

IL1RN

AW083357

6.77

interleukin 1 receptor antagonist

INDO

M34455.1

4.52

indoleamine-pyrrole 2,3 dioxygenase

INPP1

NM_002194.2

1.56

inositol polyphosphate-1-phosphatase

IRF2

NM_002199.2

2.06

interferon regulatory factor 2

IRF4

NM_002460.1

1.74

interferon regulatory factor 4

IRF7

NM_004030.1

4.37

interferon regulatory factor 7

ISG20

NM_002201.2

6.26

interferon stimulated gene 20kDa

ISGF3G

NM_006084.1

1.56

interferon-stimulated transcription factor 3, gamma 48kDa

JAK2

AF001362.1

3.22

Janus kinase 2 (a protein tyrosine kinase)

KARS

AF285758.1

1.3

lysyl-tRNA synthetase

KCNE1L

NM_012282.1

4.6

potassium voltage-gated channel, Isk-related family, member 1-like

KCNJ2

AF153820.1

3

potassium inwardly-rectifying channel, subfamily J, member 2

KLRD1

U30610.1

1.52

killer cell lectin-like receptor subfamily D, member 1

KPNB1

L38951.1

1.7

karyopherin (importin) beta 1

LAG3

NM_002286.3

3.56

lymphocyte-activation gene 3

LAMP2

J04183.1

1.74

lysosomal-associated membrane protein 2

LAMP3

NM_014398.1

3.19

lysosomal-associated membrane protein 3

LAP3

NM_015907.1

3.88

leucine aminopeptidase 3

LDLR

NM_000527.2

1.85

low density lipoprotein receptor (familial hypercholesterolemia)

LGALS3BP

NM_005567.2

3.62

lectin, galactoside-binding, soluble, 3 binding protein

LGALS9

NM_009587.1

4.65

lectin, galactoside-binding, soluble, 9 (galectin 9)

LGP2

NM_024119.1

5.6

likely ortholog of mouse D11lgp2

LLT1

NM_013269.1

2.43

lectin-like NK cell receptor

LPIN2

U55968

1.63

lipin 2

LRRFIP2

NM_006309.1

1.35

leucine rich repeat (in FLII) interacting protein 2

LY6E

NM_002346.1

8.43

lymphocyte antigen 6 complex, locus E

MAGED2

AF320070.1

2.11

melanoma antigen, family D, 2

MARCKS

AW163148

2

myristoylated alanine-rich protein kinase C substrate

MCL1

NM_021960.1

1.79

myeloid cell leukemia sequence 1 (BCL2-related)

MDA5

NM_022168.1

5.96

melanoma differentiation associated protein-5

MEF2A

X63381.1

1.57

MADS box transcription enhancer factor 2, polypeptide A

MEL

BC002977.1

1.59

mel transforming oncogene (derived from cell line NK14)- RAB8 homolog

MICA

NM_000247.1

1.43

MHC class I polypeptide-related sequence A

MICB

NM_005931.1

1.73

MHC class I polypeptide-related sequence B

MKRN1

NM_013446.1

1.46

makorin, ring finger protein, 1

MLCB

NM_006471.1

1.32

myosin, light polypeptide, regulatory, non-sarcomeric (20kD)

MNDA

NM_002432.1

6.21

myeloid cell nuclear differentiation antigen

MRPL42

BE782148

1.64

mitochondrial ribosomal protein L42

MRPS28

NM_014018.1

1.37

mitochondrial ribosomal protein S28

MRS3/4

NM_031212.1

1.69

putative mitochondrial solute carrier

MTHFD2

NM_006636.2

1.54

methylene tetrahydrofolate dehydrogenase (NAD+ dependent),

MX1

NM_002462.1

7.3

myxovirus (influenza virus) resistance 1,

MX2

NM_002463.1

5.66

myxovirus (influenza virus) resistance 2 (mouse)

MYD88

U70451.1

1.56

myeloid differentiation primary response gene (88)

N4BP1

NM_014664.1

2.24

Nedd4 binding protein 1

NAGK

NM_017567.1

1.85

N-acetylglucosamine kinase

NAPA

NM_003827.1

2.37

N-ethylmaleimide-sensitive factor attachment protein, alpha

NAT1

NM_000662.1

1.29

N-acetyltransferase 1 (arylamine N-acetyltransferase)

NBS1

AI796269

3.26

Nijmegen breakage syndrome 1 (nibrin)

NDP52

BC004130.1

1.32

nuclear domain 10 protein

NFE2L3

NM_004289.3

2.09

nuclear factor (erythroid-derived 2)-like 3

NMI

NM_004688.1

2.84

N-myc (and STAT) interactor

NMT1

AF020500.1

1.38

N-myristoyltransferase 1

NR4A3

U12767.1

3.69

nuclear receptor subfamily 4, group A, member 3

NY-REN-34

BF055474

2.31

putative zinc finger protein NY-REN-34 antigen

OAS1

NM_002534.1

14.3

2`,5`-oligoadenylate synthetase 1, 40/46kDa

OAS2

NM_016817.1

5.13

2`-5`-oligoadenylate synthetase 2, 69/71kDa

OAS3

NM_006187.1

11.88

2`-5`-oligoadenylate synthetase 3, 100kDa

OASL

NM_003733.1

6.14

2`-5`-oligoadenylate synthetase-like

OGFR

NM_007346.1

1.34

opioid growth factor receptor

ORC3L

AF125507.1

1.28

origin recognition complex, subunit 3-like (yeast)

P2RX7

NM_002562.1

2.86

purinergic receptor P2X, ligand-gated ion channel, 7

P5-1

NM_006674.1

1.38

MHC class I region ORF

PC4

NM_006713.1

1.42

activated RNA polymerase II transcription cofactor 4

PCTAIRE2BP

AW129593

3.11

tudor repeat associator with PCTAIRE 2

PDGFRL

NM_006207.1

6.54

platelet-derived growth factor receptor-like

PDZ-GEF1

NM_014247.1

1.79

PDZ domain containing guanine nucleotide exchange factor(GEF)1

PELI1

NM_020651.2

1.81

pellino homolog 1 (Drosophila)

PFKP

NM_002627.1

1.57

phosphofructokinase, platelet

PIP3-E

AW166711

1.77

phosphoinositide-binding protein PIP3-E

PKD2

AF309082.1

1.86

protein kinase D2

PLAC8

NM_016619.1

1.91

placenta-specific 8

PLEK

NM_002664.1

2.01

pleckstrin

PLSCR1

AI825926

3.43

phospholipid scramblase 1

PMAIP1

AI857639

2.33

phorbol-12-myristate-13-acetate-induced protein 1

PML

AF230411.1

6.78

promyelocytic leukemia

PMSCL1

NM_005033.1

1.83

polymyositis/scleroderma autoantigen 1, 75kDa

POLS

NM_006999.2

1.42

polymerase (DNA directed) sigma

PORIMIN

BG538627

1.51

pro-oncosis receptor inducing membrane injury gene

PPP1CC

NM_002710.1

1.37

protein phosphatase 1, catalytic subunit, gamma isoform

PPP2R2A

NM_002717.1

1.51

protein phosphatase 2 (formerly 2A), regulatory subunit B (PR 52), alpha isoform

PPP3CC

NM_005605.1

1.42

protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoform (calcineurin A gamma)

PRDX4

NM_006406.1

1.66

peroxiredoxin 4

PRF1

AI445650

1.82

Perforin, mRNA sequence

PRKAG2

NM_016203.1

1.57

protein kinase, AMP-activated, gamma 2 non-catalytic subunit

PRKR

NM_002759.1

3.3

protein kinase, interferon-inducible double stranded RNA dependent

PSCD1

NM_004762.1

1.32

pleckstrin homology, Sec7 and coiled/coil domains 1(cytohesin 1)

PSMA2

NM_002787.1

1.61

proteasome (prosome, macropain) subunit, alpha type, 2

PSMA3

NM_002788.1

1.59

proteasome (prosome, macropain) subunit, alpha type, 3

PSMA4

NM_002789.1

1.58

proteasome (prosome, macropain) subunit, alpha type, 4

PSMA5

NM_002790.1

1.53

proteasome (prosome, macropain) subunit, alpha type, 5

PSMA6

BC002979.1

1.56

proteasome (prosome, macropain) subunit, alpha type, 6

PSMB10

NM_002801.1

1.63

proteasome (prosome, macropain) subunit, beta type, 10

PSMB2

NM_002794.1

1.34

proteasome (prosome, macropain) subunit, beta type, 2

PSMB8

U17496.1

2.03

proteasome (prosome, macropain) subunit, beta type, 8 (large multifunctional protease 7)

PSMB9

NM_002800.1

2.07

proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional protease 2)

PSMC2

NM_002803.1

1.21

proteasome (prosome, macropain) 26S subunit, ATPase, 2

PSME1

NM_006263.1

1.53

proteasome (prosome, macropain) activator subunit 1 (PA28 alpha)

PSME2

NM_002818.1

1.77

proteasome (prosome, macropain) activator subunit 2 (PA28 beta)

PTS

NM_003641.1

2.62

6-pyruvoyltetrahydropterin synthase

QKI

AI114716

1.54

homolog of mouse quaking QKI (KH domain RNA binding protein)

RAB7L1

BC002585.1

1.49

RAB7, member RAS oncogene family-like 1

RALB

BG169673

1.75

v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)

RAN

AF054183.1

1.22

RAN, member RAS oncogene family

RANBP20

AL546600

1.22

RAN binding protein 20

RANGAP1

NM_002883.1

1.44

Ran GTPase activating protein 1

RARRES3

NM_004585.2

1.38

retinoic acid receptor responder (tazarotene induced) 3

RBM7

NM_016090.1

1.52

RNA binding motif protein 7

RDX

AI057093

1.96

radixin

RFX5

AW027312

1.56

regulatory factor X, 5 (influences HLA class II expression)

RGL

AF186779.1

2.01

RalGDS-like gene

RGS1

S59049.1

3.85

B cell activation gene [Homo sapiens], mRNA sequence

RI58

N47725

4.49

retinoic acid- and interferon-inducible protein (58kD)

RICH1

NM_018054.1

1.49

homolog of rat nadrin

RIG-I

NM_014314.1

6.22

DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide

RIPK1

U50062.1

1.85

receptor (TNFRSF)-interacting serine-threonine kinase 1

RIPK2

AF064824.1

2.09

receptor-interacting serine-threonine kinase 2

RPLP2

NM_001444.1

2.01

ribosomal protein, large P2

SAMHD1

NM_015474.1

1.72

SAM domain and HD domain 1

SAMSN1

NM_022136.1

1.4

SAM domain, SH3 domain and nuclear localisation signals, 1

SAT

BE971383

2.47

spermidine/spermine N1-acetyltransferase

SC4MOL

AV704962

1.7

sterol-C4-methyl oxidase-like

SCARB2

NM_005506.1

1.8

scavenger receptor class B, member 2

SCO2

NM_005138.1

2.51

SCO cytochrome oxidase deficient homolog 2 (yeast)

SEC5

NM_018303.1

1.44

homolog of yeast Sec5

SERPINB1

NM_030666.1

1.86

serine (or cysteine) proteinase inhibitor, clade B (ovalbumin), member 1

SERPING1

NM_000062.1

7.73

serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1,

SH3GLB1

AF263293.1

1.5

SH3-domain GRB2-like endophilin B1

SIAT9

NM_003896.1

1.63

sialyltransferase 9 (CMP-NeuAc:lactosylceramide alpha-2,3-sialyltransferase)

SLC37A1

NM_018964.1

2.49

solute carrier family 37 (glycerol-3-phosphate transporter), member 1

SMC6

NM_024624.1

1.32

SMC6 protein

SN

NM_023068.1

132.52

sialoadhesin

SNX11

NM_013323.1

1.76

sorting nexin 11

SNX6

NM_021249.1

1.48

sorting nexin 6

SOAT1

L21934.2

1.71

sterol O-acyltransferase (acyl-Coenzyme A: cholesterol acyltransferase) 1

SOCS1

AB005043.1

1.96

suppressor of cytokine signaling 1

SOCS2

AB004903.1

2.01

suppressor of cytokine signaling 2

SOS1

AA700167

1.59

son of sevenless homolog 1 (Drosophila)

SP100

NM_003113.1

2.52

nuclear antigen Sp100

SP110

AF280094.1

2.49

SP110 nuclear body protein

SP140

NM_007237.1

1.74

SP140 nuclear body protein

SPTLC2

U15555.1

3.06

serine palmitoyltransferase, long chain base subunit 2

SQRDL

NM_021199.1

1.81

sulfide dehydrogenase like (yeast)

SRI

L12387.1

1.28

sorcin

SSA1

NM_003141.1

1.98

Sjogren syndrome antigen A1 (52kDa, ribonucleoprotein autoantigen SS-A/Ro)

SSB

BG532929

1.51

Sjogren syndrome antigen B (autoantigen La)

STARD7

NM_020151.1

1.26

START domain containing 7

STAT1

BC002704.1

3.27

signal transducer and activator of transcription 1, 91kDa

STAT2

S81491

3.81

Stat2 type a

STAU

AJ132258.1

1.3

staufen, RNA binding protein (Drosophila)

STX11

AF071504.1

3.06

syntaxin 11

SUCLG2

BF593940

1.33

succinate-CoA ligase, GDP-forming, beta subunit

SYNGR2

NM_004710.1

1.51

synaptogyrin 2

TANK

NM_004180.1

1.41

TRAF family member-associated NFKB activator

TAP1

NM_000593.2

3.66

transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)

TARBP1

NM_005646.1

2.29

TAR (HIV) RNA binding protein 1

TBC1D1

AB029031.1

1.31

TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1

TCTEL1

NM_006519.1

3.12

t-complex-associated-testis-expressed 1-like 1

TEL2

AF147782.1

1.99

transcription factor ets

TFEC

NM_012252.1

3.38

transcription factor EC

TIA1

NM_022037.1

1.56

TIA1 cytotoxic granule-associated RNA binding protein

TINF2

NM_012461.1

1.49

TERF1 (TRF1)-interacting nuclear factor 2

TLR7

NM_016562.1

3.07

toll-like receptor 7

TNFAIP6

AW188198

5.55

tumor necrosis factor, alpha-induced protein 6

TNFRSF6

X83493.1

2.64

tumor necrosis factor receptor superfamily, member 6

TNFSF10

AW474434

9

tumor necrosis factor (ligand) superfamily, member 10

TNFSF6

D38122.1

1.54

tumor necrosis factor (ligand) superfamily, member 6

TOP1

J03250.1

1.52

topoisomerase (DNA) I

TOR1B

AF317129.1

2.26

torsin family 1, member B (torsin B)

TPO

AA164751

2.9

EST

TRADD

L41690.1

1.58

TNFRSF1A-associated via death domain

TRAF1

NM_005658.1

1.62

TNF receptor-associated factor 1

TREX1

NM_016381.1

4.05

three prime repair exonuclease 1

TRIM14

NM_014788.1

2.03

tripartite motif-containing 14

TRIM22

AA083478

2.65

tripartite motif-containing 22

TRIM26

NM_003449.1

1.56

tripartite motif-containing 26

TRIM34

NM_021616.1

2.07

tripartite motif-containing 34

TRIM38

AI363270

2.25

tripartite motif-containing 38

TRIM5

AF220028.1

3.07

tripartite motif-containing 5

TXNDC

AL080080.1

1.66

thioredoxin domain containing

TXNIP

AA812232

1.53

thioredoxin interacting protein

UBC

M26880.1

1.31

ubiquitin C

UBE1L

NM_003335.1

1.69

ubiquitin-activating enzyme E1-like

UBE2L6

NM_004223.1

2.51

ubiquitin-conjugating enzyme E2L 6

UBQLN2

AK001029.1

1.39

ubiquilin 2

UNC93B1

NM_030930.1

2.87

unc-93 homolog B1 (C. elegans)

USP15

AF153604.1

2.08

ubiquitin specific protease 15

USP18

NM_017414.1

10.43

ubiquitin specific protease 18

USP25

NM_013396.1

1.54

ubiquitin specific protease 25

UTRN

NM_007124.1

1.87

utrophin (homologous to dystrophin)

UVRAG

NM_003369.1

1.65

UV radiation resistance associated gene

VAMP5

NM_006634.1

1.48

vesicle-associated membrane protein 5 (myobrevin)

WARS

NM_004184.2

2.92

tryptophanyl-tRNA synthetase

WASPIP

NM_003387.2

1.4

Wiskott-Aldrich syndrome protein interacting protein

ZBP1

NM_030776.1

3.5

Z-DNA binding protein 1

ZFD25

NM_016220.1

1.8

zinc finger protein (ZFD25)

ZNF147

NM_005082.1

2.65

zinc finger protein 147 (estrogen-responsive finger protein)

ZNF267

AU150728

1.55

clone NT2RP7015789, highly similar to Zinc finger protein 267

ZNF313

NM_018683.1

1.55

zinc finger protein 313

 

Supplementary table 2 ( down-regulated genes)

 

GeneSymbol

Genbank

Fold Change

Description

ABCC4

AI948503

0.57

ATP-binding cassette, sub-family C (CFTR/MRP), member 4

ACADVL

NM_000018.1

0.75

acyl-Coenzyme A dehydrogenase, very long chain

ACTN1

BC003576.1

0.46

actinin, alpha 1

ACTR2

AA699583

0.80

ARP2 actin-related protein 2 homolog (yeast)

ADAM9

NM_003816.1

0.65

a disintegrin and metalloproteinase domain 9 (meltrin gamma)

ADFP

BC005127.1

0.47

adipose differentiation-related protein

AHNAK

BG287862

0.57

AHNAK nucleoprotein (desmoyokin)

AK1

BC001116.1

0.58

adenylate kinase 1

AKAP13

M90360.1

0.77

A kinase (PRKA) anchor protein 13

AKR7A2

AI144075

0.73

aldo-keto reductase family 7, member A2 (aflatoxin aldehyde reductase)

ALDOA

AK026577.1

0.75

aldolase A, fructose-bisphosphate

ALOX5

AA995910

0.60

arachidonate 5-lipoxygenase

AMT

NM_000481.1

0.69

aminomethyltransferase (glycine cleavage system protein T)

ANPEP

NM_001150.1

0.57

alanyl (membrane) aminopeptidase

AP1S2

AF251295.1

0.55

adaptor-related protein complex 1, sigma 2 subunit

AP2M1

NM_004068.1

0.75

adaptor-related protein complex 2, mu 1 subunit

AP2S1

BC006337.1

0.69

adaptor-related protein complex 2, sigma 1 subunit

APLP2

BC004371.1

0.50

amyloid beta (A4) precursor-like protein 2

APOE

AI358867

0.51

apolipoprotein E

ARF5

NM_001662.2

0.78

ADP-ribosylation factor 5

ARHGDIB

NM_001175.1

0.80

Rho GDP dissociation inhibitor (GDI) beta

ARHGEF7

NM_003899.1

0.66

Rho guanine nucleotide exchange factor (GEF) 7

ASB1

AF055024.1

0.77

ankyrin repeat and SOCS box-containing 1

ATP1A1

NM_000701.1

0.78

ATPase, Na+/K+ transporting, alpha 1 polypeptide

ATP2B4

AW517686

0.69

ATPase, Ca++ transporting, plasma membrane 4

ATP5L

AL050277.1

0.80

ATP synthase, H+ transporting, mitochondrial F0 complex, subunit g

ATP5O

NM_001697.1

0.79

ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit

ATP9B

AW411030

0.72

ATPase, Class II, type 9B

AUTS2

AK025298.1

0.70

autism susceptibility candidate 2

BCKDK

NM_005881.1

0.74

branched chain alpha-ketoacid dehydrogenase kinase

BCL11B

NM_022898.1

0.76

B-cell CLL/lymphoma 11B (zinc finger protein)

BDG-29

AB011151.1

0.56

BDG-29 proten

BNIP3L

AL132665.1

0.72

BCL2/adenovirus E1B 19kDa interacting protein 3-like

C11orf2

NM_013265.2

0.62

chromosome 11 open reading frame2

C12orf10

NM_021640.1

0.74

chromosome 12 open reading frame 10

C18orf1

NM_004338.1

0.58

chromosome 18 open reading frame 1

C1orf37

AL522296

0.72

chromosome 1 open reading frame 37

C1QR1

NM_012072.2

0.33

complement component 1, q subcomponent, receptor 1

C21orf97

NM_021941.1

0.48

chromosome 21 open reading frame 97

CACNA1I

AB032946.1

0.73

calcium channel, voltage-dependent, alpha 1I subunit

CALU

NM_001219.2

0.69

calumenin

CCL22

NM_002990.1

0.61

chemokine (C-C motif) ligand 22

CCNI

AF135162.1

0.78

cyclin I

CD14

NM_000591.1

0.29

CD14 antigen

CD44

BE903880

0.68

CD44 antigen (homing function and Indian blood group system)

CD7

AI829961

0.45

CD7 antigen (p41)

CD9

NM_001769.1

0.32

CD9 antigen (p24)

CDC14B

AU145941

0.72

CDC14 cell division cycle 14 homolog B (S. cerevisiae)

CERK

NM_022766.1

0.52

ceramide kinase

CHD3

U91543.1

0.68

chromodomain helicase DNA binding protein 3

ChGn

NM_018371.1

0.55

chondroitin beta1,4 N-acetylgalactosaminyltransferase

CIZ1

AF234161.1

0.69

Cip1-interacting zinc finger protein

CKLF1

NM_016326.2

0.66

chemokine-like factor 1

CLECSF5

NM_013252.1

0.11

C-type (calcium dependent, carbohydrate-recognition domain) lectin, superfamily member 5

CLECSF6

NM_016184.1

0.48

C-type (calcium dependent, carbohydrate-recognition domain) lectin, superfamily member 6

CLTB

NM_001834.1

0.72

clathrin, light polypeptide (Lcb)

CLTC

NM_004859.1

0.78

clathrin, heavy polypeptide (Hc)

COPA

U24105.1

0.74

coatomer protein complex, subunit alpha

COPZ1

NM_016057.1

0.74

CGI-120 protein

COX4I1

AA854966

0.70

cytochrome c oxidase subunit IV isoform 1

COX7C

AA382702

0.75

cytochrome c oxidase subunit VIIc

CREBL2

NM_001310.1

0.69

cAMP responsive element binding protein-like 2

CRELD1

NM_015513.1

0.76

cysteine-rich with EGF-like domains 1

CRY1

D83702.1

0.68

cryptochrome 1 (photolyase-like)

CSF1R

NM_005211.1

0.43

colony stimulating factor 1 receptor

CSNK2B

M30448.1

0.59

Human casein kinase II beta subunit mRNA, complete cds.

CSPG2

BF590263

0.15

chondroitin sulfate proteoglycan 2 (versican)

CTNND1

AB002382.1

0.59

catenin (cadherin-associated protein), delta 1

CTSB

AA020826

0.50

cathepsin B

CUTL1

BE046521

0.58

cut-like 1, CCAAT displacement protein (Drosophila)

CXCL5

AK026546.1

0.20

chemokine (C-X-C motif) ligand 5

CYBB

NM_000397.2

0.52

cytochrome b-245, beta polypeptide (chronic granulomatous disease)

DAD1

NM_001344.1

0.75

defender against cell death 1

DDB1

L40326.1

0.76

damage-specific DNA binding protein 1, 127kDa

DEFCAP

AF229061.1

0.72

death effector filament-forming Ced-4-like apoptosis protein

DGAT1

NM_012079.2

0.50

diacylglycerol O-acyltransferase homolog 1 (mouse)

DP1

BC000232.1

0.78

likely ortholog of mouse deleted in polyposis 1

DREV1

NM_016025.1

0.63

CGI-81 protein

DSTN

NM_006870.2

0.76

destrin (actin depolymerizing factor)

DUSP3

AL048503

0.57

dual specificity phosphatase 3 (vaccinia virus phosphatase VH1-related)

EEF1B2

NM_001959.1

0.65

eukaryotic translation elongation factor 1 beta 2

EEF1D

AI613383

0.54

eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange protein)

EEF1G

AF119850.1

0.63

eukaryotic translation elongation factor 1 gamma

EEF2

NM_001961.1

0.65

eukaryotic translation elongation factor 2

EIF3S5

NM_003754.1

0.66

eukaryotic translation initiation factor 3, subunit 5 epsilon, 47kDa

EIF3S6IP

NM_016091.1

0.49

eukaryotic translation initiation factor 3, subunit 6 interacting protein

EIF3S7

NM_003753.1

0.70

eukaryotic translation initiation factor 3, subunit 7 zeta, 66/67kDa

EIF4B

NM_001417.1

0.54

eukaryotic translation initiation factor 4B

EIF4G3

AI768122

0.73

eukaryotic translation initiation factor 4 gamma, 3

EMR3

AF239764.1

0.29

egf-like module-containing mucin-like receptor 3

ENG

NM_000118.1

0.50

endoglin (Osler-Rendu-Weber syndrome 1)

ENO2

NM_001975.1

0.59

enolase 2, (gamma, neuronal)

EP400

BE880591

0.74

E1A binding protein p400

EVI2B

BC005926.1

0.76

ecotropic viral integration site 2B

FADS3

NM_021727.1

0.61

fatty acid desaturase 3

FAU

NM_001997.1

0.76

 ribosomal protein S30

FBXO9

AL031178

0.75

clone 341E18 on chromosome 6p11.2-12.3. Contains a SerineThreonine Protein Kinase gene

FLNA

NM_001456.1

0.70

filamin A, alpha (actin binding protein 280)

FPR1

NM_002029.1

0.23

formyl peptide receptor 1

FTH1

AA083483

0.50

ferritin, heavy polypeptide 1

FURIN

NM_002569.1

0.62

furin (paired basic amino acid cleaving enzyme)

FXYD5

NM_014164.2

0.53

FXYD domain containing ion transport regulator 5

FYN

S74774.1

0.72

FYN oncogene related to SRC, FGR, YES

GABARAP

NM_007278.1

0.76

GABA(A) receptor-associated protein

GALC

NM_000153.1

0.66

galactosylceramidase (Krabbe disease)

GALNT1

U41514.1

0.77

UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1

GALNT11

NM_022087.1

0.65

UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 11

GALNT6

NM_007210.2

0.51

UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6

GAPD

AK026525.1

0.62

glyceraldehyde-3-phosphate dehydrogenase

GAS7

BE439987

0.57

growth arrest-specific 7

GLA

NM_000169.1

0.71

galactosidase, alpha

GLTSCR2

NM_015710.1

0.68

glioma tumor suppressor candidate region gene 2

GNA12

AK024696.1

0.67

guanine nucleotide binding protein (G protein) alpha 12

GNB2L1

NM_006098.1

0.69

guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1

GPI

NM_000175.1

0.59

glucose phosphate isomerase

GS3955

NM_021643.1

0.65

GS3955 protein

GTF2I

AF035737.1

0.73

general transcription factor II, i

H2AV

BF343852

0.58

histone H2A.F/Z variant

H3F3A

AA477655

0.76

H3 histone, family 3A

HADHA

BG472176

0.68

hydroxyacyl-Coenzyme A dehydrogenase/ alpha subunit

HADHSC

NM_005327.1

0.72

L-3-hydroxyacyl-Coenzyme A dehydrogenase, short chain

HIC2

AL043112

0.68

hypermethylated in cancer 2

HIP1

NM_005338.3

0.49

huntingtin interacting protein 1

HNRPA0

BE966599

0.76

heterogeneous nuclear ribonucleoprotein A0

HPIP

BF344265

0.77

hematopoietic PBX-interacting protein

HS3ST1

NM_005114.1

0.32

heparan sulfate (glucosamine) 3-O-sulfotransferase 1

IDS

NM_006123.1

0.74

iduronate 2-sulfatase (Hunter syndrome)

IGF1R

AI830698

0.49

Human insulin-like growth factor 1 receptor mRNA, 3` sequence

IL4R

NM_000418.1

0.74

interleukin 4 receptor

IRS2

BF700086

0.61

insulin receptor substrate 2

ITGAM

NM_000632.2

0.60

integrin, alpha M (complement component receptor 3, alpha)

ITGB2

NM_000211.1

0.59

integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1

ITM2A

NM_004867.1

0.67

integral membrane protein 2A

KATNB1

NM_005886.1

0.75

katanin p80 (WD40-containing) subunit B 1

KCNAB2

AL520102

0.73

potassium voltage-gated channel, shaker-related subfamily, beta member 2

KDELR2

AL542253

0.80

KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 2

KLRB1

NM_002258.1

0.58

killer cell lectin-like receptor subfamily B, member 1

KRAS2

W80678

0.78

v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog

KRT10

M19156.1

0.79

keratin 10 (epidermolytic hyperkeratosis; keratosis palmaris et plantaris)

LENG4

BC003164.1

0.68

leukocyte receptor cluster (LRC) member 4

LEPROTL1

NM_015344.1

0.77

leptin receptor overlapping transcript-like 1

LGALS1

NM_002305.2

0.54

lectin, galactoside-binding, soluble, 1 (galectin 1)

LOC57209

N21541

0.61

Kruppel-type zinc finger protein

LOC64174

NM_022355.1

0.49

putative dipeptidase

LTA4H

J02959.1

0.42

leukotriene A4 hydrolase

LTBP2

NM_000428.1

0.51

latent transforming growth factor beta binding protein 2

M9

AF085358.1

0.74

muscle specific gene

MACF1

NM_012090.1

0.77

microtubule-actin crosslinking factor 1

MAEA

NM_005882.2

0.75

macrophage erythroblast attacher

MAGED1

AF217963.1

0.75

melanoma antigen, family D, 1

MAPKAP1

NM_024117.1

0.79

mitogen-activated protein kinase associated protein 1

MBC2

BC004998.1

0.63

likely ortholog of mouse membrane bound C2 domain containing protein

MECP2

NM_004992.2

0.62

methyl CpG binding protein 2 (Rett syndrome)

MIC2

NM_002414.1

0.78

antigen identified by monoclonal antibodies 12E7, F21 and O13

MMP9

NM_004994.1

0.42

matrix metalloproteinase 9

MN1

NM_002430.1

0.59

meningioma (disrupted in balanced translocation) 1

MOAP1

AK024029.1

0.77

modulator of apoptosis 1

MONDOA

NM_014938.1

0.61

Mlx interactor

MPHOSPH9

AI990326

0.67

M-phase phosphoprotein 9

MRC1

NM_002438.1

0.24

mannose receptor, C type 1

MSF

AB023208

0.78

MLL septin-like fusion

MTVR1

AF052151

0.80

Mouse Mammary Turmor Virus Receptor homolog 1

MXD4

BC002713.1

0.69

MAX dimerization protein 4

MYH9

AI827941

0.75

myosin, heavy polypeptide 9, non-muscle

NACA

BF976260

0.73

nascent-polypeptide-associated complex alpha polypeptide

NAP1L1

AW148801

0.76

nucleosome assembly protein 1-like 1

NDRG3

NM_022477.1

0.69

NDRG family member 3

NDUFS5

NM_004552.1

0.71

NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa

NELL2

NM_006159.1

0.69

NEL-like 2 (chicken)

NGFRAP1

NM_014380.1

0.58

nerve growth factor receptor (TNFRSF16) associated protein 1

NS1-BP

AF205218.1

0.69

NS1-binding protein

NTE

NM_006702.1

0.66

neuropathy target esterase

OLR1

AF035776.1

0.32

oxidised low density lipoprotein (lectin-like) receptor 1

OSBPL8

AL049923.1

0.66

oxysterol binding protein-like 8

PABPC1

AI734929

0.55

poly(A) binding protein, cytoplasmic 1

PABPC3

NM_030979.1

0.52

poly(A) binding protein, cytoplasmic 3

PABPC4

NM_003819.2

0.65

poly(A) binding protein, cytoplasmic 4 (inducible form)

PABPCP3

U64661

0.59

Human poly(A)-binding protein processed pseudogene3

PAPSS1

AF033026.1

0.74

3`-phosphoadenosine 5`-phosphosulfate synthase 1

PARL

NM_018622.1

0.72

presenilins associated rhomboid-like protein

PCSK5

NM_006200.1

0.51

proprotein convertase subtilisin/kexin type 5

PDE4A

NM_006202.1

0.60

phosphodiesterase 4A, (phosphodiesterase E2 dunce homolog, Drosophila)

PDHA1

BF739979

0.79

Homo sapiens cDNA FLJ34891 fis, clone NT2NE2017562, mRNA sequence

PFDN5

AB055804.1

0.64

prefoldin 5

PHLDA1

AA576961

0.46

pleckstrin homology-like domain, family A, member 1

PIG7

AB034747.1

0.80

LPS-induced TNF-alpha factor

PLA2G4B

N71116

0.72

phospholipase A2, group IVB (cytosolic)

PLAU

NM_002658.1

0.53

plasminogen activator, urokinase

PLP2

NM_002668.1

0.62

proteolipid protein 2 (colonic epithelium-enriched)

PLU-1

NM_006618.1

0.73

putative DNA/chromatin binding motif

PNMA1

NM_006029.2

0.62

paraneoplastic antigen MA1

PPGB

NM_000308.1

0.71

protective protein for beta-galactosidase (galactosialidosis)

PPIF

BC005020.1

0.54

peptidylprolyl isomerase F (cyclophilin F)

PPT1

NM_000310.1

0.76

palmitoyl-protein thioesterase 1 (ceroid-lipofuscinosis, neuronal 1, infantile)

PRKACA

NM_002730.1

0.39

protein kinase, cAMP-dependent, catalytic, alpha

PRKAR2A

BF246917

0.74

protein kinase, cAMP-dependent, regulatory, type II, alpha

PRKCB1

NM_002738.1

0.73

protein kinase C, beta 1

PRKCSH

AI815793

0.77

protein kinase C substrate 80K-H

PRKWNK1

AI742553

0.70

Homo sapiens, clone IMAGE:5264735, mRNA, mRNA sequence

PROCR

NM_006404.1

0.43

protein C receptor, endothelial (EPCR)

PRPF8

NM_006445.1

0.65

PRP8 pre-mRNA processing factor 8 homolog (yeast)

PSMD1

NM_002807.1

0.73

proteasome (prosome, macropain) 26S subunit, non-ATPase, 1

PTPRO

U20489.1

0.80

Human glomerular epithelial protein 1 (GLEPP1) mRNA, complete cds.

QARS

NM_005051.1

0.69

glutaminyl-tRNA synthetase

QPCT

NM_012413.2

0.46

glutaminyl-peptide cyclotransferase (glutaminyl cyclase)

QSCN6

NM_002826.2

0.58

quiescin Q6

RAB31

NM_006868.1

0.49

RAB31, member RAS oncogene family

RAB33A

NM_004794.1

0.65

RAB33A, member RAS oncogene family

RAI17

AF070622.1

0.48

retinoic acid induced 17

RANBP2

D42063.1

0.78

RAN binding protein 2

RAP2A

AI302106

0.74

RAP2A, member of RAS oncogene family

RASSF2

NM_014737.1

0.61

Ras association (RalGDS/AF-6) domain family 2

RBM8A

AF182415.1

0.73

RNA binding motif protein 8A

RCL

AF040105

0.73

putative c-Myc-responsive

RDGBB

NM_012417.1

0.64

retinal degeneration B beta

REA

NM_007273.1

0.77

repressor of estrogen receptor activity

RGC32

NM_014059.1

0.57

RGC32 protein

RLN2

NM_005059.1

0.68

relaxin 2 (H2)

ROM1

NM_000327.1

0.50

retinal outer segment membrane protein 1

RPL10

NM_006013.1

0.69

ribosomal protein L10

RPL10A

NM_007104.2

0.64

ribosomal protein L10a

RPL11

NM_000975.1

0.72

ribosomal protein L11

RPL13

AA789278

0.75

ribosomal protein L13

RPL13A

BC001675.1

0.80

ribosomal protein L13a

RPL14

U16738.1

0.77

ribosomal protein L14

RPL15

NM_002948.1

0.71

ribosomal protein L15

RPL17

NM_000985.1

0.67

ribosomal protein L17

RPL18

NM_000979.1

0.69

ribosomal protein L18

RPL18A

NM_000980.1

0.66

ribosomal protein L18a

RPL21

NM_000982.1

0.69

ribosomal protein L21

RPL22

BE250348

0.70

ribosomal protein L22

RPL23

NM_000978.1

0.68

ribosomal protein L23

RPL27

NM_000988.1

0.75

ribosomal protein L27

RPL29

BF683426

0.70

ribosomal protein L29

RPL3

L22453.1

0.63

ribosomal protein L3

RPL30

L05095.1

0.78

ribosomal protein L30

RPL31

NM_000993.1

0.73

ribosomal protein L31

RPL34

BF216701

0.77

ribosomal protein L34

RPL35

NM_007209.1

0.79

ribosomal protein L35

RPL36A

NM_021029.1

0.76

ribosomal protein L36A

RPL37A

NM_000998.1

0.80

ribosomal protein L37a

RPL38

NM_000999.1

0.75

ribosomal protein L38

RPL4

AI953886

0.56

ribosomal protein L4

RPL5

NM_000969.1

0.59

ribosomal protein L5

RPL6

NM_000970.1

0.64

ribosomal protein L6

RPL7

NM_000971.1

0.73

ribosomal protein L7

RPL7A

NM_000972.1

0.73

ribosomal protein L7a

RPL8

NM_000973.1

0.70

ribosomal protein L8

RPL9

NM_000661.1

0.76

ribosomal protein L9

RPLP0

BC003655.1

0.79

ribosomal protein, large, P0

RPS10

BC004334.1

0.75

ribosomal protein S10

RPS10L

AL118502

0.67

clone RP11-371L19 on chromosome 20

RPS11

NM_001015.1

0.74

ribosomal protein S11

RPS12

AI799007

0.79

ribosomal protein S12

RPS13

NM_001017.1

0.75

ribosomal protein S13

RPS14

AF116710.1

0.63

ribosomal protein S14

RPS15A

NM_001019.1

0.76

ribosomal protein S15a

RPS16

NM_001020.1

0.64

ribosomal protein S16

RPS17

BC004886.1

0.72

ribosomal protein S17

RPS18

NM_022551.1

0.78

ribosomal protein S18

RPS19

BE259729

0.74

EST, Weakly similar to I52692 ribosomal protein S19, cytosolic

RPS2

AA630314

0.79

ribosomal protein S2

RPS20

NM_001023.1

0.78

ribosomal protein S20

RPS21

NM_001024.1

0.72

ribosomal protein S21

RPS23

NM_001025.1

0.77

ribosomal protein S23

RPS25

AA888388

0.76

ribosomal protein S25

RPS27A

NM_002954.1

0.61

ribosomal protein S27a

RPS28

BC000354.1

0.79

ribosomal protein S28

RPS3

U14990.1

0.73

ribosomal protein S3

RPS3A

AI925635

0.78

ribosomal protein S3A

RPS4X

NM_001007.1

0.74

ribosomal protein S4, X-linked

RPS5

NM_001009.1

0.62

ribosomal protein S5

RPS6

BC000524.1

0.76

ribosomal protein S6

RPS6KA1

NM_002953.1

0.76

ribosomal protein S6 kinase, 90kDa, polypeptide 1

RPS7

AI970731

0.69

ribosomal protein S7

RPS9

NM_001013.1

0.71

ribosomal protein S9

RTN3

NM_006054.1

0.56

reticulon 3

RUNX1

D43968.1

0.63

runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)

RXRA

NM_002957.2

0.50

retinoid X receptor, alpha

S100A10

NM_002966.1

0.65

S100 calcium binding protein A10 (annexin II ligand, calpactin I, light polypeptide (p11))

S100A12

NM_005621.1

0.31

S100 calcium binding protein A12 (calgranulin C)

S100A4

NM_002961.2

0.38

S100 calcium binding protein A4 (calcium protein, calvasculin, murine placental homolog)

S100A6

NM_014624.2

0.54

S100 calcium binding protein A6 (calcyclin)

S100A8

NM_002964.2

0.40

S100 calcium binding protein A8 (calgranulin A)

S100A9

NM_002965.2

0.37

S100 calcium binding protein A9 (calgranulin B)

SCA1

AW235612

0.53

ESTs,  similar to  uronyl-2-sulfotransferase;

SDBCAG84

AF091085.1

0.67

serologically defined breast cancer antigen 84

SDR1

NM_004753.1

0.55

short-chain dehydrogenase/reductase 1

SEMA4C

AI949392

0.39

sema domain, immunoglobulin domain (Ig), transmembrane domain ™

SGNE1

NM_003020.1

0.42

secretory granule, neuroendocrine protein 1 (7B2 protein)

SGPL1

BE999972

0.66

sphingosine-1-phosphate lyase 1

SH3BGRL3

NM_031286.1

0.64

SH3 domain binding glutamic acid-rich protein like 3

SH3BP5

AL562152

0.71

SH3-domain binding protein 5 (BTK-associated)

SIRT2

NM_012237.2

0.69

sirtuin silent mating type information regulation 2 homolog 2 (S. cerevisiae)

SKI

AI568728

0.64

v-ski sarcoma viral oncogene homolog (avian)

SLC11A1

D50402.1

0.45

solute carrier family 11 (proton-coupled divalent metal ion transporters), member 1

SLC16A10

NM_018593.1

0.17

solute carrier family 16 (monocarboxylic acid transporters), member 10

SLC25A6

AA916851

0.73

solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 6

SLC2A3

NM_006931.1

0.67

solute carrier family 2 (facilitated glucose transporter), member 3

SLC7A11

AB040875.1

0.35

solute carrier family 7, (cationic amino acid transporter, y+ system) member 11

SNRPD2

NM_004597.3

0.75

small nuclear ribonucleoprotein D2 polypeptide 16.5kDa

SORL1

NM_003105.2

0.63

sortilin-related receptor, L(DLR class) A repeats-containing

SOS2

AI628605

0.69

ESTs

SPON1

AB018305.1

0.59

spondin 1, (f-spondin) extracellular matrix protein

SSR2

NM_003145.2

0.79

signal sequence receptor, beta (translocon-associated protein beta)

STAB1

D87433

0.30

stabilin 1

STX10

NM_003765.1

0.73

syntaxin 10

SULT1A1

NM_001055.1

0.73

sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1

SVIL

NM_003174.2

0.71

supervillin

TACC1

NM_006283.1

0.77

transforming, acidic coiled-coil containing protein 1

TBXAS1

NM_030984.1

0.27

thromboxane A synthase 1 (platelet, cytochrome P450, subfamily V)

TC10

AW771590

0.70

ras-like protein TC10

TCF20

AB006630.1

0.74

transcription factor 20 (AR1)

TGFBI

NM_000358.1

0.21

transforming growth factor, beta-induced, 68kDa

TGM2

AL031651

0.52

clone RP5-1054A22 on chromosome 20q11.22-12 Contains two isoforms of the gene for TGM2

TIMP1

NM_003254.1

0.24

tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor)

TIP-1

AF234997.1

0.67

Tax interaction protein 1

TLE3

AI567426

0.76

transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila)

TLN1

NM_006289.1

0.66

talin 1

TMP21

BE780075

0.80

transmembrane trafficking protein

TNFRSF8

NM_001243.1

0.57

tumor necrosis factor receptor superfamily, member 8

TNFSF13

AF114012.1

0.65

tumor necrosis factor (ligand) superfamily, member 13

TOM7

NM_019059.1

0.68

homolog of Tom7 (S. cerevisiae)

TOP2B

NM_001068.1

0.76

topoisomerase (DNA) II beta 180kDa

TREM1

NM_018643.1

0.36

triggering receptor expressed on myeloid cells 1

TTC3

NM_003316.1

0.66

tetratricopeptide repeat domain 3

TUBGCP2

NM_006659.1

0.69

tubulin, gamma complex associated protein 2

TUFM

NM_003321.1

0.75

Tu translation elongation factor, mitochondrial

TULIP1

AL050050.1

0.72

likely ortholog of mouse tuberin-like protein 1

UAP1

S73498.1

0.74

UDP-N-acteylglucosamine pyrophosphorylase 1

UBA52

AF348700.1

0.77

ubiquitin A-52 residue ribosomal protein fusion product 1

UBE4B

NM_006048.1

0.63

ubiquitination factor E4B (UFD2 homolog, yeast)

UCP2

U94592.1

0.72

Human uncoupling protein homolog (UCPH) mRNA, complete cds.

UGTREL7

N80922

0.73

UDP-glucuronic acid/UDP-N-acetylgalactosamine dual transporter

UMP-CMPK

NM_016308.1

0.73

UMP-CMP kinase

UP

NM_003364.1

0.60

uridine phosphorylase

UQCRB

NM_006294.1

0.61

ubiquinol-cytochrome c reductase binding protein

USF2

NM_003367.1

0.48

upstream transcription factor 2, c-fos interacting

USP13

NM_003940.1

0.70

ubiquitin specific protease 13 (isopeptidase T-3)

UXT

NM_004182.1

0.67

ubiquitously-expressed transcript

VAMP1

NM_016830.1

0.70

vesicle-associated membrane protein 1 (synaptobrevin 1)

VDR

NM_000376.1

0.54

vitamin D (1,25- dihydroxyvitamin D3) receptor

VIM

AI922599

0.79

vimentin

VRP

BC001663.1

0.70

vascular Rab-GAP/TBC-containing

WBSCR5

AF257135.1

0.59

Williams-Beuren syndrome chromosome region 5

WHSC1

AF083389.1

0.74

Wolf-Hirschhorn syndrome candidate 1

WRB

NM_004627.1

0.62

tryptophan rich basic protein

XAP135

NM_018288.1

0.74

PHD zinc finger protein XAP135

YF13H12

NM_014297.1

0.78

protein expressed in thyroid

Z39IG

NM_007268.1

0.27

Ig superfamily protein

ZDHHC7

NM_017740.1

0.78

zinc finger, DHHC domain containing 7

ZFP106

NM_022473.1

0.70

zinc finger protein 106

ZNF220

NM_006766.1

0.77

zinc finger protein 220

ZNF91

NM_003430.1

0.71

zinc finger protein 91 (HPF7, HTF10)