The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines

Methylation of CpG sites in the control regions of tumor suppressor genes may be an important mechanism for their heritable, yet reversible, transcriptional inactivation. These changes in methylation may impair the proper expression and/or function of cell cycle regulatory genes and confer a selecti...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 1998-03, Vol.58 (6), p.1245-1252
Hauptverfasser: GONZALGO, M. L, HAYASHIDA, T, BENDER, C. M, PAO, M. M, TSAI, Y. C, GONZALES, F. A, NGUYEN, H. D, NGUYEN, T. T, JONES, P. A
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container_end_page 1252
container_issue 6
container_start_page 1245
container_title Cancer research (Chicago, Ill.)
container_volume 58
creator GONZALGO, M. L
HAYASHIDA, T
BENDER, C. M
PAO, M. M
TSAI, Y. C
GONZALES, F. A
NGUYEN, H. D
NGUYEN, T. T
JONES, P. A
description Methylation of CpG sites in the control regions of tumor suppressor genes may be an important mechanism for their heritable, yet reversible, transcriptional inactivation. These changes in methylation may impair the proper expression and/or function of cell cycle regulatory genes and confer a selective growth advantage to affected cells. Detailed methylation analysis using genomic bisulfite sequencing was performed on a series of subclones of a bladder cancer cell line in which a hypermethylated p16 gene had been reactivated by transient treatment with 5-aza-2'-deoxycytidine. Methylation of the CpG island in the promoter of the p16 gene in human bladder cancer cells did not stop the formation of a transcript initiated 20 kb upstream by the p19 promoter but did prevent the expression of a p16 transcript. Furthermore, we show that reactivant clones that expressed p16 at varying levels contained heterogeneous methylation patterns, suggesting that p16 expression can occur even in the presence of a relatively heavily methylated coding region. We also present the first functional evidence that methylation of only a small number of CpG sites can significantly down-regulate p16 promoter activity, thus providing support for the model of progressive inactivation of this tumor suppressor gene by DNA methylation.
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L ; HAYASHIDA, T ; BENDER, C. M ; PAO, M. M ; TSAI, Y. C ; GONZALES, F. A ; NGUYEN, H. D ; NGUYEN, T. T ; JONES, P. A</creator><creatorcontrib>GONZALGO, M. L ; HAYASHIDA, T ; BENDER, C. M ; PAO, M. M ; TSAI, Y. C ; GONZALES, F. A ; NGUYEN, H. D ; NGUYEN, T. T ; JONES, P. A</creatorcontrib><description>Methylation of CpG sites in the control regions of tumor suppressor genes may be an important mechanism for their heritable, yet reversible, transcriptional inactivation. These changes in methylation may impair the proper expression and/or function of cell cycle regulatory genes and confer a selective growth advantage to affected cells. Detailed methylation analysis using genomic bisulfite sequencing was performed on a series of subclones of a bladder cancer cell line in which a hypermethylated p16 gene had been reactivated by transient treatment with 5-aza-2'-deoxycytidine. Methylation of the CpG island in the promoter of the p16 gene in human bladder cancer cells did not stop the formation of a transcript initiated 20 kb upstream by the p19 promoter but did prevent the expression of a p16 transcript. Furthermore, we show that reactivant clones that expressed p16 at varying levels contained heterogeneous methylation patterns, suggesting that p16 expression can occur even in the presence of a relatively heavily methylated coding region. 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ispartof Cancer research (Chicago, Ill.), 1998-03, Vol.58 (6), p.1245-1252
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source MEDLINE; American Association for Cancer Research; Free E-Journal (出版社公開部分のみ)
subjects Azacitidine - pharmacology
Biological and medical sciences
Carrier Proteins - genetics
Cell Cycle Proteins
CpG Islands
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p19
DNA Methylation
Down-Regulation
Gene Expression Regulation, Neoplastic
Genes, p16
Humans
Medical sciences
Nephrology. Urinary tract diseases
Promoter Regions, Genetic
Transcription, Genetic
Tumor Cells, Cultured
Tumors of the urinary system
Urinary Bladder Neoplasms - genetics
Urinary tract. Prostate gland
title The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines
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