This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Peterson, E. J. Articles by Taylor, S. M. Search for Related Content PubMed PubMed Citation Articles by Peterson, E. J. Articles by Taylor, S. M.

p53-Mediated Repression of DNA Methyltransferase 1 Expression by Specific DNA Binding¹

Departments of Biology and Microbiology & Immunology [E. J. P., S. M. T.] and Massey Cancer Center [S. M. T.], Virginia Commonwealth University, Richmond, Virginia 23298, and William and Karen Davidson Laboratory of Brain Tumor Biology, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202 [O. B.]

Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG island methylation has been implicated in tumor suppressor gene silencing. Here we demonstrate a mechanistic link between the p53tumor suppressor gene and control of epigenetic regulation by genomic methylation. Deletion of p53in HCT116 human colon carcinoma cells and primary mouse astrocytes resulted in a 6-fold increase of DNA cytosine methyltransferase 1 (Dnmt1) mRNA and protein, suggesting relief of p53-mediated Dnmt1repression. A p53 consensus binding site in exon 1 of the human Dnmt1gene bound recombinant p53 in vitro and endogenous p53 in vivo in the absence of stimuli that activate p53, implying that p53 controls Dnmt1transcription through direct DNA binding. Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels. Our findings suggest that activation of p53 reduces binding and relieves transcriptional repression of the Dnmt1gene, whereas loss of p53, a frequent, early event in tumorigenesis, may significantly contribute to aberrant genomic methylation.

This article has been cited by other articles:

				F. M. Muggia, G. J. Peters, and J. R. Landolph Jr. XIII International Charles Heidelberger Symposium and 50 Years of Fluoropyrimidines in Cancer Therapy Held on September 6 to 8, 2007 at New York University Cancer Institute, Smilow Conference Center Mol. Cancer Ther., May 1, 2009; 8(5): 992 - 999. [Abstract] [Full Text] [PDF]

				M. Rossi, O. N. Demidov, C. W. Anderson, E. Appella, and S. J. Mazur Induction of PPM1D following DNA-damaging treatments through a conserved p53 response element coincides with a shift in the use of transcription initiation sites Nucleic Acids Res., December 1, 2008; 36(22): 7168 - 7180. [Abstract] [Full Text] [PDF]

				G. Dhar, S. Banerjee, K. Dhar, O. Tawfik, M. S. Mayo, P. J. VanVeldhuizen, and S. K. Banerjee Gain of Oncogenic Function of p53 Mutants Induces Invasive Phenotypes in Human Breast Cancer Cells by Silencing CCN5/WISP-2 Cancer Res., June 15, 2008; 68(12): 4580 - 4587. [Abstract] [Full Text] [PDF]

				M. A. Knowles Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis, March 1, 2006; 27(3): 361 - 373. [Abstract] [Full Text] [PDF]

				P.-O. Esteve, H. G. Chin, and S. Pradhan Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters PNAS, January 25, 2005; 102(4): 1000 - 1005. [Abstract] [Full Text] [PDF]

				Y.-C. Wang, R.-K. Lin, Y.-H. Tan, J.-T. Chen, C.-Y. Chen, and Y.-C. Wang Wild-Type p53 Overexpression and Its Correlation With MDM2 and p14ARF Alterations: An Alternative Pathway to Non-Small-Cell Lung Cancer J. Clin. Oncol., January 1, 2005; 23(1): 154 - 164. [Abstract] [Full Text] [PDF]