Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation

Ge Zhou, Jiping Wang, Mei Zhao, Tong Xin Xie, Noriaki Tanaka, Daisuke Sano, Ameeta A. Patel, Alexandra M. Ward, Vlad C. Sandulache, Samar A. Jasser, Heath D. Skinner, Alison Lea Fitzgerald, Abdullah A. Osman, Yongkun Wei, Xuefeng Xia, Zhou Songyang, Gordon Mills, Mien Chie Hung, Carlos Caulin, Jiyong LiangJeffrey N. Myers

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.

Original languageEnglish (US)
Pages (from-to)960-974
Number of pages15
JournalMolecular Cell
Volume54
Issue number6
DOIs
Publication statusPublished - Jun 19 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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