p53-mediated down-regulation of the human DNA repair gene O 6-methylguanine-DNA methyltransferase (MGMT) via interaction with Sp1 transcription factor

Dora Bocangel, Shiladitya Sengupta, Sankar Mitra, Kishor K. Bhakat

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

O6-Methylguanine-DNA methyltransferase (MGMT), a ubiquitous DNA repair protein, reverses mutagenic and cytotoxic effects of O 6-alkylguanine in DNA induced by chemotherapeutic N-alkyl N-nitrosourea and procarbazine type drugs by dealkylating the adduct. MGMT expression is down-regulated by wild-type p53 (WTp53) in human tumor cells. Here we report that p53 sequesters the Sp1 transcription factor to prevent its binding to the cognate eis elements in the MGMT promoter and thus inhibits MGMT expression. Sp1 overexpression abrogated the inhibitory effect of p53 on the MGMT promoter activity in a dose-dependent manner. Stable interaction of Sp1 with WTp53 was observed in HCT116 cells. Moreover, WTp53 overexpression reduced the binding of the nuclear extract to the Sp1 consensus sequence, even though recombinant p53 alone did not bind to the same sequence. Taken together, these results suggest that sequestration of Sp1 could be one of the mechanisms by which p53 negatively regulates MGMT expression, thus enhancing sensitivity of tumor cells to O6-alkylguanine generating drugs.

Original languageEnglish (US)
Pages (from-to)3741-3750
Number of pages10
JournalAnticancer Research
Volume29
Issue number10
StatePublished - Oct 2009

Keywords

  • Alkylating agent
  • DNA repair
  • Drug resistance
  • MGMT
  • Sp1 transcription factor
  • p53

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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