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

被引：185

作者：

Zhou, Ge ^{[1
]}

Wang, Jiping ^{[1
]}

Zhao, Mei ^{[1
]}

Xie, Tong-Xin ^{[1
]}

Tanaka, Noriaki ^{[1
]}

Sano, Daisuke ^{[1
]}

Patel, Ameeta A. ^{[1
]}

Ward, Alexandra M. ^{[1
]}

Sandulache, Vlad C. ^{[1
]}

Jasser, Samar A. ^{[1
]}

Skinner, Heath D. ^{[1
]}

Fitzgerald, Alison Lea ^{[1
]}

Osman, Abdullah A. ^{[1
]}

Wei, Yongkun ^{[2
]}

Xia, Xuefeng ^{[5
,6
]}

Zhou Songyang ^{[7
,8
]}

Mills, Gordon B. ^{[3
]}

Hung, Mien-Chie ^{[2
,9
,10
]}

Caulin, Carlos ^{[1
,4
]}

Liang, Jiyong ^{[3
]}

Myers, Jeffrey N. ^{[1
,5
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[6] Methodist Hosp, Ctr Diabet Res, Res Inst, Houston, TX 77030 USA

[7] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA

[8] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510275, Guangdong, Peoples R China

[9] China Med Univ, Grad Inst Canc Biol, Taichung 404, Taiwan

[10] China Med Univ, Ctr Mol Med, Taichung 404, Taiwan

来源：

MOLECULAR CELL | 2014年 / 54卷 / 06期

关键词：

PROTEIN-KINASE; ENERGY SENSOR; STRESS; HEAD; PHOSPHORYLATES; LOCALIZATION; MUTATIONS; REGULATOR; DISEASE; TARGET;

D O I：

10.1016/j.molcel.2014.04.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 AMPK alpha 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.

引用

页码：960 / 974

页数：15

共 46 条

[1] Gain-of-function mutant p53 but not p53 deletion promotes head and neck cancer progression in response to oncogenic K-ras [J].

Acin, Sergio ;

Li, Zhongyou ;

Mejia, Olga ;

Roop, Dennis R. ;

El-Naggar, Adel K. ;

Caulin, Carlos .

JOURNAL OF PATHOLOGY, 2011, 225 (04) :479-489

[2] Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1 [J].

Agrawal, Nishant ;

Frederick, Mitchell J. ;

Pickering, Curtis R. ;

Bettegowda, Chetan ;

Chang, Kyle ;

Li, Ryan J. ;

Fakhry, Carole ;

Xie, Tong-Xin ;

Zhang, Jiexin ;

Wang, Jing ;

Zhang, Nianxiang ;

El-Naggar, Adel K. ;

Jasser, Samar A. ;

Weinstein, John N. ;

Trevino, Lisa ;

Drummond, Jennifer A. ;

Muzny, Donna M. ;

Wu, Yuanqing ;

Wood, Laura D. ;

Hruban, Ralph H. ;

Westra, William H. ;

Koch, Wayne M. ;

Califano, Joseph A. ;

Gibbs, Richard A. ;

Sidransky, David ;

Vogelstein, Bert ;

Velculescu, Victor E. ;

Papadopoulos, Nickolas ;

Wheeler, David A. ;

Kinzler, Kenneth W. ;

Myers, Jeffrey N. .

SCIENCE, 2011, 333 (6046) :1154-1157

[3] Metabolic Regulation by p53 Family Members [J].

Berkers, Celia R. ;

Maddocks, Oliver D. K. ;

Cheung, Eric C. ;

Mor, Inbal ;

Vousden, Karen H. .

CELL METABOLISM, 2013, 18 (05) :617-633

[4] Heterozygosity for Hypoxia Inducible Factor 1α Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model [J].

Bertout, Jessica A. ;

Patel, Shetal A. ;

Fryer, Benjamin H. ;

Durham, Amy C. ;

Covello, Kelly L. ;

Olive, Kenneth P. ;

Goldschmidt, Michael H. ;

Simon, M. Celeste .

CANCER RESEARCH, 2009, 69 (07) :3213-3220

[5] p53 target genes Sestrin1 and Sestrin2 connect genotoxic stress and mTOR signaling [J].

Budanov, Andrei V. ;

Karin, Michael .

CELL, 2008, 134 (03) :451-460

[6] Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? [J].

DeBerardinis, Ralph J. ;

Thompson, Craig B. .

CELL, 2012, 148 (06) :1132-1144

[7] S-Adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet [J].

Esfandiari, Farah ;

You, Min ;

Villanueva, Jesus A. ;

Wong, Donna H. ;

French, Samuel W. ;

Halsted, Charles H. .

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2007, 31 (07) :1231-1239

[8] AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo [J].

Faubert, Brandon ;

Boily, Gino ;

Izreig, Said ;

Griss, Takla ;

Samborska, Bozena ;

Dong, Zhifeng ;

Dupuy, Fanny ;

Chambers, Christopher ;

Fuerth, Benjamin J. ;

Viollet, Benoit ;

Mamer, Orval A. ;

Avizonis, Daina ;

DeBerardinis, Ralph J. ;

Siegel, Peter M. ;

Jones, Russell G. .

CELL METABOLISM, 2013, 17 (01) :113-124

[9] The regulation of AMPK β1, TSC2, and PTEN expression by p53:: Stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways [J].

Feng, Zhaohui ;

Hu, Wenwei ;

de Stanchina, Elisa ;

Teresky, Angelika K. ;

Jin, Shengkan ;

Lowe, Scott ;

Levine, Arnold J. .

CANCER RESEARCH, 2007, 67 (07) :3043-3053

[10] The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein [J].

Feng, Zhaohui ;

Levine, Arnold J. .

TRENDS IN CELL BIOLOGY, 2010, 20 (07) :427-434

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