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

104 Citations (Scopus)

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
StatePublished - Jun 19 2014
Externally publishedYes

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AMP-Activated Protein Kinases
Mutant Proteins
Growth
Neoplasms
Ribosomal Protein S6
Acetyl-CoA Carboxylase
Protein Subunits
Head and Neck Neoplasms
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation. / Zhou, Ge; Wang, Jiping; Zhao, Mei; Xie, Tong Xin; Tanaka, Noriaki; Sano, Daisuke; Patel, Ameeta A.; Ward, Alexandra M.; Sandulache, Vlad C.; Jasser, Samar A.; Skinner, Heath D.; Fitzgerald, Alison Lea; Osman, Abdullah A.; Wei, Yongkun; Xia, Xuefeng; Songyang, Zhou; Mills, Gordon; Hung, Mien Chie; Caulin, Carlos; Liang, Jiyong; Myers, Jeffrey N.

In: Molecular Cell, Vol. 54, No. 6, 19.06.2014, p. 960-974.

Research output: Contribution to journalArticle

Zhou, G, Wang, J, Zhao, M, Xie, TX, Tanaka, N, Sano, D, Patel, AA, Ward, AM, Sandulache, VC, Jasser, SA, Skinner, HD, Fitzgerald, AL, Osman, AA, Wei, Y, Xia, X, Songyang, Z, Mills, G, Hung, MC, Caulin, C, Liang, J & Myers, JN 2014, 'Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation', Molecular Cell, vol. 54, no. 6, pp. 960-974. https://doi.org/10.1016/j.molcel.2014.04.024
Zhou, Ge ; Wang, Jiping ; Zhao, Mei ; Xie, Tong Xin ; Tanaka, Noriaki ; Sano, Daisuke ; Patel, Ameeta A. ; Ward, Alexandra M. ; Sandulache, Vlad C. ; Jasser, Samar A. ; Skinner, Heath D. ; Fitzgerald, Alison Lea ; Osman, Abdullah A. ; Wei, Yongkun ; Xia, Xuefeng ; Songyang, Zhou ; Mills, Gordon ; Hung, Mien Chie ; Caulin, Carlos ; Liang, Jiyong ; Myers, Jeffrey N. / Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation. In: Molecular Cell. 2014 ; Vol. 54, No. 6. pp. 960-974.
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