P53 mutants induce transcription of NF-κB2 in H1299 cells through CBP and STAT binding on the NF-κB2 promoter and gain of function activity

Catherine A. Vaughan, Shilpa Singh, Brad Windle, Heidi M. Sankala, Paul R. Graves, W. Andrew Yeudall, Swati P. Deb, Sumitra Deb

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Cancer cells with p53 mutations, in general, grow more aggressively than those with wild-type p53 and show "gain of function" (GOF) phenotypes such as increased growth rate, enhanced resistance to chemotherapeutic drugs, increased cell motility and tumorigenicity; although the mechanism for this function remains unknown. In this communication we report that p53-mediated NF-κB2 up-regulation significantly contributes to the aggressive oncogenic behavior of cancer cells. Lowering the level of mutant p53 in a number of cancer cell lines resulted in a loss of GOF phenotypes directly implicating p53 mutants in the process. RNAi against NF-κB2 in naturally occurring cancer cell lines also lowers GOF activities. In H1299 cells expressing mutant p53, chromatin immunoprecipitation (ChIP) assays indicate that mutant p53 induces histone acetylation at specific sites on the regulatory regions of its target genes. ChIP assays using antibodies against transcription factors putatively capable of interacting with the NF-κB2 promoter show increased interaction of CBP and STAT2 in the presence of mutant p53. Thus, we propose that in H1299 cells, mutant p53 elevates expression of genes capable of enhancing cell proliferation, motility, and tumorigenicity by inducing acetylation of histones via recruitment of CBP and STAT2 on the promoters causing CBP-mediated histone acetylation.

Original languageEnglish (US)
Pages (from-to)79-88
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume518
Issue number1
DOIs
StatePublished - Feb 1 2012

Keywords

  • Gain of function
  • Mutant p53
  • Transactivation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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