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J. Biol. Chem., Vol. 276, Issue 43, 39508-39511, October 26, 2001

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ACCELERATED PUBLICATION
Interleukin-6 Regulation of the Human DNA Methyltransferase (HDNMT) Gene in Human Erythroleukemia Cells^*

David R. Hodge^§¶, Weihua Xiao^§, Peter A. Clausen, Gisela Heidecker^**, Moshe Szyf, and William L. Farrar^§

From the  Intramural Research Support Program, SAIC Frederick and the Cytokine Molecular Mechanisms Section, ^§ Laboratory of Molecular Immunoregulation, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702, the  Invitrogen Corporation, Gaithersburg, Maryland 20852, the ^** Laboratory of Leukocyte Biology, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702, and the  Department of Pharmacology, McGill University, Montreal, Quebec H3G 1Y6, Canada

Received for publication, June 21, 2001, and in revised form, September 7, 2001

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Methylation of mammalian DNA by the DNA methyltransferase enzyme (dnmt-1) at CpG dinucleotide sequences has been recognized as an important epigenetic control mechanism in regulating the expression of cellular genes (Yen, R. W., Vertino, P. M., Nelkin, B. D., Yu, J. J., el-Deiry, W., Cumaraswamy, A., Lennon, G. G., Trask, B. J., Celano, P., and Baylin, S. B. (1992) Nucleic Acids Res. 20, 2287-2291; Ramchandani, S., Bigey, P., and Szyf, M. (1998) Biol. Chem. 379, 535-5401). Here we show that interleukin (IL)-6 regulates the methyltransferase promoter and resulting enzyme activity, which requires transcriptional activation by the Fli-1 transcription factor (Spyropoulos, D. D., Pharr, P. N., Lavenburg, K. R., Jackers, P., Papas, T. S., Ogawa, M., and Watson, D. K. (1998) Mol. Cell. Biol. 15, 5643-5652). The data suggest that inflammatory cytokines such as IL-6 may exert many epigenetic changes in cells via the regulation of the methyltransferase gene. Furthermore, IL-6 regulation of transcription factors like Fli-1, which can help to direct cells along opposing differentiation pathways, may in fact be reflected in part by their ability to regulate the methylation of cellular genes.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The transfer of a methyl group to the cytosine portion of the CpG dinucleotide by dnmt-1 permits or enables the binding of methyl-specific DNA-binding proteins to the methylated CpG site (1, 2, 4, 5). The binding of methyl-specific proteins such as MeCP1 and MeCP2 to genetic regulatory elements represses transcription by blocking the binding of other positive acting transactivation factors (6). Methylcytosine-DNA-binding proteins can attract histone deacetylases to the site, which remodel chromatin into highly repressed states (7). Thus, DNA methylation can result in permanent epigenetic alteration of genes and is important in promoting or guiding the differentiation of cells and the establishment of tissue-specific gene expression patterns (8).

The inflammatory cytokine IL-6¹ is able to induce the maturation and differentiation of cells (9). Treatment of the human erythroleukemia cell line K562 with IL-6 induces the expression of megakaryocytic markers and the silencing of certain globin genes (10). Derived from an acute erythroblastic leukemia, K562 cells are multipotent in that they can be directed into two separate differentiation pathways (11). K562 cells express low levels of both erythrocytic- and megakaryocytic-specific genetic markers and can be induced to differentiate along one of these two major pathways depending upon the external stimuli applied to the cells (12, 13). This ability suggests some form of epigenetic control over the differentiation process. The ETS family of transcription factors represent a large family of differentially expressed, positive and negative regulators of transcription and are involved in cell differentiation (3). Here we show that when K562 cells are induced to enter the megakaryocytic differentiation pathway by IL-6, an increase in Fli-1 expression occurs, which results in the transactivation of the human methyltransferase-1 gene expression.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Cell Culture-- COS-1 cells were obtained from the American Type Culture Collection (CRL-1650) and maintained in Dulbecco's modified Eagle's medium high glucose supplemented with 10% FBS, glutamine, and penicillin-streptomycin solutions. Human erythroleukemia K562 cells (ATCC CCL-243) were maintained in RPMI 1640 medium supplemented with 10% FBS, glutamine, and penicillin-streptomycin solutions. Recombinant interleukin-6 (catalog number 200-06) was purchased from Pepro-Tech Inc. (Rocky Hill, NJ). For IL-6 stimulation, K562 cells were collected by centrifugation, rinsed twice in phosphate-buffered saline, pH 7.4, then resuspended in RPMI 1640 medium supplemented with glutamine, penicillin-streptomycin, and 0.05% FBS for 48 h, then treated with IL-6.

Methylation Assay-- Cell nuclear pellets were freeze-thawed three times and centrifuged to remove debris. Clarified lysates were mixed with an equal volume of Chelex-100 resin (50%v/v) to remove DNA and RNA from the sample. For each replicate, 5 µg of the protein lysate was added to 200 µl of an assay mixture consisting of 20 mM Tris-HCl, pH 7.4, 5 mM EDTA, 25% glycerol, 0.5% Triton X-100, 1 mM dithiothreitol, 0.2 mM phenylmethylsulfonyl fluoride, 5 µCi of S-adenosyl-L-[methyl-³H]methionine (12 Ci/mmol), 4 µg of poly(dI-dC), and 200 µg/ml bovine serum albumin and incubated at 37 °C for 2 h. Incorporated label was assessed by scintillation counting.

Reverse Transcription-PCR Assays-- cDNAs for each gene were prepared from TriZOL (Life Technologies, Inc.) extracted total RNAs. reverse transcription reactions were run on 2 µg of total RNA. Following reverse transcription reactions, PCR reactions were run to the midpoint of each PCR fragment's linear synthesis curve. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) bands on agarose gels were scanned on a STORM^TM Scanner (Molecular Dynamics) to ensure equalization of expression levels at each time point. Primers for the HDNMT-1 gene (GenBank^TM accession number X63692) were 5'-AAGTGAAGCCCGTAGAGTG-3', nt 579-598 (sense) and 5'-TTCTCATCCTGGTCTTTGT-3', nt 827-846 (antisense), which yielded a 267-bp fragment, while primers specific for the Fli-1 gene (GenBank^TM accession number M98833) were 5'-CGCCACCACCCTCTACAACACGGAA-3', nt 703-728 (sense), and 5'-CGGGCCCAGGATCTGATACGGATCT-3', nt 952-977 (antisense), which yielded a 274-bp fragment. Amplification primers specific for the GAPDH gene (sense 5'-AGGTGAAGGTCGGAGTCAACGG-3' and antisense 5'-CCCAGCCTTCTCCATGGTGGTG-3') were utilized to amplify a constitutively expressed internal control fragment of 319 bp.

Luciferase Assays-- Cells were incubated for 36 h and then harvested, lysed in 1× luciferase lysis buffer (20 mM Tris-Cl, pH 7.8, 1% Triton X-100 (v/v), 0.1 mM EDTA, 1 mM dithiothreitol added just prior to use), and 200 µl of medium was removed for a normalization assay using the CLONTECH pSEAP positive control vector and CSPD^TM chemiluminescent substrate kit (CSPD^TM disodium 3-(4-methoxyspiro[1,2-dioxetane-3,2'-(5-chloro)tricyclo[3.3.1.1-3,7]-decan]-4-yl)phenyl phosphate catalog number K-2041-1) prior to lysis. Experiments to determine luciferase activity for each condition were run in triplicate and normalized against CSPD^TM substrate assay values per microgram of protein to ensure consistent transfection levels between experiments. hdnmt-1 promoter constructs in pGL-3 basic luciferase reporter vector were generated by PCR utilizing the following primer sets: wild-type MT1 construct, 5'-CGGCTAGCCGGAATTCGCCCTTTGGTGTAA-3' (MT1), 5'-CCAAGCTTGGAAGACCCTGCCTCACTCTGT-3' (MT2); MT2 (1214 to +71 bp), 5'-CGGCTAGCCGGTGACAGAGTGAGGCAGGGT-3'(MT3), 5'-CCAAGCTTGGGGAAGATCACTTGAACCGGA-3' (MT4); MT3 (815 to +71 bp), 5'-CGGCTAGCCGCTCAACCTCTGGAGTAGTTT-3' (MT5), 5'-CCAAGCTTGGTTGCCACCTACTCTAGAAAA-3' (MT6); MT4 (474 to +71), 5'-CGGCTAGCCGGAGTAGGTGGCAATTACCCC-3' (MT7), 5'-CCAAGCTTGGTCCAAGCTCCACGTTTCCTG-3' (MT8); and MT5 (243 to +71 bp), 5'-CGGCTAGCCGGAGCTTGGACGAGCCCACTC-3' (MT9), 5'-CCAAGCTTGGATTCGCCCTTACATCGTCGG-3' (MT10).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

We examined the effect of IL-6 treatment on methyltransferase activity by using K562 cells in a rested state in RPMI 1640 medium supplemented with 0.05% FBS for ~48 h. The cells were rinsed twice in serum-free RPMI 1640 and then treated with IL-6 (at 100 ng/ml). After 8-h incubation, the cells were harvested, and methylation activity assays were performed as described previously (14) to determine the relative levels of activity following IL-6 treatment. Lanes 1 and 2 in Fig. 1 show the results obtained from control reactions utilizing only cell lysates with no poly(dI-dC)·poly(dI-dC) substrate added and poly(dI-dC)·poly(dI-dC) substrate with no cell lysates added, respectively. Lane 3 represents the basal level of methylation activity obtained from rested K562 cells, while lane 4 shows a 3.2-fold increase in activity following treatment with IL-6. Based on these observations, treatment with IL-6 appears to increase overall methylation activity.

View larger version (21K): [in this window] [in a new window]   Fig. 1.   Methylation activity assay. Cells were rested 48 h, then treated with IL-6 at 100 ng/ml, or carrier as described, and incubated for 8 h. Activity of methyltransferase in K562 cells was determined by measuring incorporation of label into poly(dI-dC)·poly(dI-dC) substrate. Lane 1, cell lysate without poly(dI-dC)·poly(dI-dC); lane 2, poly(dI-dC)·poly(dI-dC) without cell lysate; lane 3, methylation activity of unstimulated K562 cells; lane 4, IL-6-stimulated K562 cells. IL-6 induces increased methylation activity as shown by incorporated 3H counts.

To determine whether treatment with IL-6 activates the hdnmt-1 promoter, we generated a series of deletion constructs as shown in Fig. 2A. The constructs were sequenced and used to transfect K562 cells, which were rested prior to stimulation with IL-6 as described above. Gradual deletion of increasing amounts of the wild-type promoter as shown in lane 1 (MT1), lane 2 (MT2) (1214 to +71 bp), lane 3 (MT3) (-815 to +71 bp), and lane 4 (MT4) (474 to +71) did not abrogate the IL-6-induced activity. The results shown in Fig. 2B, lane 5, indicate that IL-6-induced promoter activity is localized to the MT5 segment (243 to +71 bp), which encodes several potential ETS family recognition sites. Fig. 2C, lane 1, shows the results of transfecting wild-type MT5 and then stimulating with IL-6. Unstimulated wild-type MT5 reporter levels are represented in lane 2. Fig. 2C, lanes 3 and 4, show the activity levels of a MT5 triple-mutant reporter stimulated with IL-6 and unstimulated, respectively. The ETS site-mutated MT5 reporter shows a markedly suppressed response, as the loss of the three Fli-1 binding sites in MT5 abrogated the IL-6-mediated response.

View larger version (23K): [in this window] [in a new window]   Fig. 2.   A, hdnmt-1 promoter constructs in pGL-3 Basic luciferase reporter vector. Methyltransferase I (HDNMT-1) promoter region spanning nucleotides 248-1950 from the published complete genomic clone sequence. Nucleotides encoding restriction endonuclease sites for NheI and HindIII were included in the 5' ends of PCR primers used to generate various promoter deletion constructs. Primers used to construct promoter deletions are described under "Experimental Procedures." B, activation of hdnmt-1 promoter by IL-6 stimulation of K562 cells. Cells were transfected with 2 µg of plasmid by Fugene-6 reagent and allowed to incubate overnight. Cells were then rinsed in PBS, pH 7.4, and resuspended in resting medium as described. After 48 h, IL-6 was added, and cells were harvested the following morning (16 h). Lane 1, MT1; lane 2, MT2 (1214 to +71 bp); lane 3, MT3 (815 to +71 bp); lane 4, MT4 (474 to +71); lane 5, MT5 (243 to +71 bp). IL-6-induced promoter activity is localized to the  MT5 (243 to +71 bp) segment. C, transactivation of hdnmt-1 MT5 reporter in IL-6-stimulated K562 cells. K562 cells were stimulated with IL-6 24 h post-transfection with wild-type and mutated MT-5 luciferase reporter plasmid. Lanes 1 and 2, transfected with wild-type MT5 plasmid: lane 1, treated with IL-6; lane 2, no IL-6. Lanes 3 and 4, transfected with Fli-1 binding site triple-mutated MT5 plasmid: lane 3, treated with IL-6; lane 4, no IL-6.

To determine whether IL-6 induced increased expression of hdnmt-1 and Fli-1 mRNA, K562 cells were incubated in RPMI 1640 medium supplemented with 0.05% FBS for ~48 h. The cells were rinsed twice in serum-free RPMI 1640 and then treated with IL-6 at a concentration of 100 ng/ml. Treated cells were collected at 0, 1, 2, 4, 6, 8, 12, and 24 h post-treatment with IL-6. Total cellular RNA was prepared at each time point and stored at 70 °C. Ultraviolet spectroscopy was used to quantitate equally each RNA sample, and final working dilutions for each time point were rechecked following initial dilution to a concentration of 100 ng/µl. The adjusted total RNA preparations were then used to create cDNA, on which PCR reactions were performed. Using primers specific for hdnmt-1 and Fli-1, PCR was performed for each time point to determine the relative expression level of each gene. The temporal expression pattern of hdnmt-1 is shown in Fig. 3A. The expression of hdnmt-1 begins to appear at 6 h post-treatment, reaching a peak between 8 and 12 h. At 24 h, hdnmt-1 mRNA is still expressed, but the level is considerably diminished. The double-banded PCR product seen for the hdnmt-1 is due to an intronic insertion, and the PCR primers were chosen to amplify this region to determine whether both possible gene products are affected equally by IL-6 (15). In K562 cells, no difference in expression levels between the two possible hdnmt-1 mRNA products were noted.

View larger version (98K): [in this window] [in a new window]   Fig. 3.   Reverse transcription-PCR analysis of IL-6-treated K562 cells. A, hdnmt-1 22 cycles; B, Fli-1 20 cycles; C, GAPDH 18 cycles; at 94 °C for 30 s, 60 °C for 45 s, and 72 °C for 45 s.

The ETS family transcription factor, Fli-1, which is known to be expressed in megakaryocytic lineages as a mediator of differentiation (16), begins to be expressed at ~4 h post-treatment (Fig. 3B) and continues to increase throughout the sampling period. The expression pattern of the prototypic ETS family member, Ets-1, did not show a response to IL-6 when cDNA from the rested K562 cells was analyzed in parallel reactions with hdnmt-1 and Fli-1, and Ets-1 did not produce a discernable band when the reactions were analyzed at the midpoint of the amplification curve (data not shown.) Fig. 3C shows equivalent expression levels of the GAPDH gene cDNA control at each time point.

Analysis of the MT5 promoter elements reveals three potential Fli-1 binding sites at 194, 170, and 60 base pairs (17). A series of singular and multiple point mutations of the MT5 constructs, shown in Fig. 4a, were co-transfected into COS-1 cells with pSG5Fli-1 expression plasmid to determine the authenticity of each potential ETS binding site. Fig. 4b shows the strongest activation with all three potential Fli-1 binding sites left intact. The intact promoter construct MT5-WT (lane 1) is transactivated nearly 29-fold over the triple mutant MT5-25 (lane 8), which shows merely 2-fold activation over background. The other point-mutated MT5 constructs showed varying degrees of activity, which suggests an additive effect for each site, with the constructs containing only single site mutations (MT5-20 (lane 3), MT5-22 (lane 5), and MT5-23 (lane 6), showing the most activity when compared with those constructs receiving two combined site mutations MT5-19 (lane 2), MT5-21 (lane 4), and MT5-24 (lane 7)). The mutation of the double ETS binding sites (194 and 170) in the MT5-24 construct (lane 7) produced nearly the same effect as the triple mutant, with a 5-fold increase in activity compared with 2-fold for the triple mutant.

View larger version (60K): [in this window] [in a new window]   Fig. 4.   a, site-specific mutations introduced into hdnmt-1 promoter region containing putative Fli-1 binding sites. Mutations are shown in bold text for each site. b, identification of putative Fli-1 binding sites by site-specific mutagenesis. Lane 1, MT5, wild-type; lane 2, MT5-19; lane 3, MT5-20; lane 4, MT5-21; lane 5, MT5-22; lane 6, MT5-23; lane 7, MT5-24; lane 8, MT5-25, triple mutant. c depicts luciferase activity (-fold activation) of corresponding mutations (shown as black bars) in putative Fli-1 binding sites.

These results provide evidence of a novel mechanism of IL-6 cytokine-mediated alteration, via the Fli-1 transcription factor, of methyltransferase gene expression. Previously, it was shown that IL-6 activation of the immediate-early gene junB occurred through an ETS family protein, in cooperation with a CREB-ATF factor (18). An analogous situation exists in fos-transformed cells, in which the expression of DNA methyltransferase is three times that of normal levels (19). Thus, it has been proposed that fos transformation is mediated by increased methyltranferase expression. Therefore, by analogy, even slight alterations in methyltransferase expression resulting from chronic exposure to IL-6 could, over time, result in abnormal patterns of cellular DNA methylation, similar to those caused by transformation of fos. Indeed, the importance of dnmt-1 activity in the establishment and propagation of neoplastic growth has emerged as an important diagnostic factor (20). Methylated CpG dinucleotides are susceptible to spontaneous deamination of 5-methylcytosine to uracil and are believed to be responsible for approximately one-third of C-T transition mutations found in human genetic diseases and tumors (21). Hypermethylation of tumor suppressor genes such as p53 (22), retinoblastoma (Rb) (23), and p16^ink (24) occur in many different tumors types, serving to promote tumor growth by rendering these genes inactive. The effects of promiscuous methylation of important tumor suppressor and cell cycle regulatory genes potentially resulting from prolonged exposure to inflammatory cytokines are probably cumulative in nature, remaining latent until sufficient insult to the cell permits it to transform into a neoplastic growth (25).

We demonstrate here that IL-6, an inflammatory cytokine capable of mediating cellular differentiation, is capable of increasing DNA methytransferase expression and activity. The data suggest that one of the normal molecular consequences of the biological activity of IL-6 may be mediated by DNA methyltransferase activity modifying gene expression. Additionally, IL-6 has been implicated in numerous cancer models, including multiple myeloma and prostate carcinoma (26,27). However, in a few cell lines, IL-6 has shown inhibitory effects on tumorigenesis (28) and anti-inflammatory capacity (29). Notwithstanding these pleiotropic characteristics, chronic exposure of cells to inflammatory cytokines such as IL-6 may have serious consequences by altering the normal levels, or time of expression of many genes, by up-regulating methyltransferase, whose expression is normally tightly controlled in a cell cycle-dependent manner (30, 31). Dysregulation of DNA methyltransferase may result in the methylation of important tumor suppressor and cell cycle regulatory genes eventually initiating or enhancing neoplastic growth (32, 33).

	ACKNOWLEDGEMENT

We are very grateful to Dr. Joost Oppenheim for his critical review of the manuscript.

	FOOTNOTES

^* This work was supported in whole or in part with Federal funds from the NCI, National Institutes of Health, under Contract NO1-CO-56000 and sponsored in part by the NCI, Department of Health and Human Services, under a contract with SAIC. The content of this publication does not necessarily reflect the views or policies of the Department of Health and human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: NCI, NIH, P. O. Box B, Bldg. 560, Rm. 31-76, Frederick, MD 21702. Tel.: 301-846-6865; Fax: 301-846-7042; E-mail: hodge@mail.ncifcrf.gov.

Published, JBC Papers in Press, September 10, 2001, DOI 10.1074/jbc.C100343200

	ABBREVIATIONS

The abbreviations used are: IL, interleukin; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; nt, nucleotide(s); bp, base pair(s).

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 276/43/39508    most recent C100343200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hodge, D. R. Articles by Farrar, W. L. Search for Related Content PubMed PubMed Citation Articles by Hodge, D. R. Articles by Farrar, W. L. Social Bookmarking                      What's this?