JBC Anatrace, Inc.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1074/jbc.M100615200 on March 21, 2001

J. Biol. Chem., Vol. 276, Issue 22, 19052-19058, June 1, 2001
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
276/22/19052    most recent
M100615200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yamada, H.
Right arrow Articles by Glick, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yamada, H.
Right arrow Articles by Glick, A.

Increased Sensitivity of Transforming Growth Factor (TGF) beta 1 Null Cells to Alkylating Agents Reveals a Novel Link between TGFbeta Signaling and O6-Methylguanine Methyltransferase Promoter Hypermethylation*

Hisaharu YamadaDagger , Kinnimulki Vijayachandra§, Carrie Penner§, and Adam Glick§

From the Dagger  Toxicology Laboratory, Pharmaceutical Research Laboratories, Taisho Pharmaceuticals, Tokyo 170-8633, Japan and § Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland, 20892

Inactivation of the transforming growth factor beta  (TGFbeta )-signaling pathway and gene silencing through hypermethylation of promoter CpG islands are two frequent alterations in human and experimental cancers. Here we report that nonneoplastic TGFbeta 1-/- keratinocyte cell lines exhibit increased sensitivity to cell killing by alkylating agents, and this is due to lack of expression of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT). In TGFbeta 1-/- but not TGFbeta 1+/- cell lines, the CpG dinucleotides in the MGMT promoter are hypermethylated, as measured by restriction enzyme analysis and methylation specific polymerase chain reaction. In one unstable TGFbeta 1+/- cell line, loss of the wild type TGFbeta 1 allele correlates with the appearance of methylation in the MGMT promoter. Bisulfite sequencing shows that in the KO3 TGFbeta 1-/- cell line nearly all of the 28 CpG sites in the MGMT promoter 475 base pairs upstream of the start site of transcription are methylated, whereas most are unmethylated in the H1 TGFbeta 1+/- line. Treatment of the TGFbeta 1-/- cell lines with 5-azacytidine causes reexpression of MGMT mRNA and demethylation of CpG islands in the promoter. Analysis of the time course of methylation using methylation-specific polymerase chain reaction shows a lack of methylation in primary TGFbeta 1-/- keratinocytes and increasing methylation with passage number of immortalized clones. Subcloning of early passage clones reveals a remarkable heterogeneity and instability of the methylation state in the TGFbeta 1-/- keratinocytes. Thus, the TGFbeta 1-/- genotype does not directly regulate MGMT methylation but predisposes cells to immortalization-associated MGMT hypermethylation.

* 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: Laboratory of Cellular Carcinogenesis and Tumor Promotion, Bldg. 37 3B19 National Cancer Institute, NIH, Bethesda, MD 20892. Tel.: 301-496-3248; Fax: 301-496-8709; E-mail: glicka@dc37a.nci.nih.gov

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


This article has been cited by other articles:


Home page
 Cancer Res.Home page
J. Kirshner, M. F. Jobling, M. J. Pajares, S. A. Ravani, A. B. Glick, M. J. Lavin, S. Koslov, Y. Shiloh, and M. H. Barcellos-Hoff
Inhibition of Transforming Growth Factor-{beta}1 Signaling Attenuates Ataxia Telangiectasia Mutated Activity in Response to Genotoxic Stress
Cancer Res., November 15, 2006; 66(22): 10861 - 10869.
[Abstract] [Full Text] [PDF]

Home page
 Jpn J Clin OncolHome page
H.-W. Chen, Y.-C. Chang, Y.-L. Lai, Y.-J. Chen, M.-J. Huang, Y.-S. Leu, Y.-K. Fu, L.-W. Wang, and J.-J. Hwang
Change of Plasma Transforming Growth Factor-{beta}1 Levels in Nasopharyngeal Carcinoma Patients Treated with Concurrent Chemo-radiotherapy
Jpn. J. Clin. Oncol., August 1, 2005; 35(8): 427 - 432.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Radiol.Home page
M H Barcellos-Hoff
How tissues respond to damage at the cellular level: orchestration by transforming growth factor-{beta} (TGF-{beta})
Br. J. Radiol., January 1, 2005; Supplement_27(1): 123 - 127.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Yoneda, T. Furukawa, Y.-J. Zheng, T. Momoi, I. Izawa, M. Inagaki, M. Manabe, and N. Inagaki
An Autocrine/Paracrine Loop Linking Keratin 14 Aggregates to Tumor Necrosis Factor {alpha}-mediated Cytotoxicity in a Keratinocyte Model of Epidermolysis Bullosa Simplex
J. Biol. Chem., February 20, 2004; 279(8): 7296 - 7303.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. B. Ewan, R. L. Henshall-Powell, S. A. Ravani, M. J. Pajares, C. Arteaga, R. Warters, R. J. Akhurst, and M. H. Barcellos-Hoff
Transforming Growth Factor-{beta}1 Mediates Cellular Response to DNA Damage in Situ
Cancer Res., October 15, 2002; 62(20): 5627 - 5631.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.