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 B. Mills; Mien Chie Hung; Carlos Caulin; Jiyong Liang; Jeffrey N. Myers

doi:10.1016/j.molcel.2014.04.024

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 B. Mills, Mien Chie Hung, Carlos Caulin, Jiyong LiangJeffrey N. Myers

Research output: Contribution to journal › Article › peer-review

187 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 language	English (US)
Pages (from-to)	960-974
Number of pages	15
Journal	Molecular Cell
Volume	54
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2014.04.024
State	Published - Jun 19 2014
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2014.04.024

Cite this

Zhou, G., Wang, J., Zhao, M., Xie, T. X., Tanaka, N., Sano, D., Patel, A. A., Ward, A. M., Sandulache, V. C., Jasser, S. A., Skinner, H. D., Fitzgerald, A. L., Osman, A. A., Wei, Y., Xia, X., Songyang, Z., Mills, G. B., Hung, M. C., Caulin, C., ... Myers, J. N. (2014). Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation. Molecular Cell, 54(6), 960-974. https://doi.org/10.1016/j.molcel.2014.04.024

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, GB, 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

@article{6c717be36efd4422a42b24b102739798,

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

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.",

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

note = "Funding Information: We thank Drs. Guillermina Lozano and Yoko Takahashi for providing p53 −/− and p53 (R172H/H) MEFs and SKBR3, UMSCC1, HN30, and Detroit 562 stable cell lines. We also thank Drs. Kun-liang Guan, Jianhua Yang, and Xiaolu Yang for providing the plasmids. This research was supported by the University Cancer Foundation via the Institutional Research Grant program at The University of Texas MD Anderson Cancer Center to G.Z. (IRG Grant Fred 35608) and by NIH grants RO1 DE015344 to C.C.; CA133249 and GM095599 to Z.S.; and RO1 DE14613, P50CA097007, and CA016672 to J.N.M. ",

year = "2014",

month = jun,

day = "19",

doi = "10.1016/j.molcel.2014.04.024",

language = "English (US)",

volume = "54",

pages = "960--974",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation

AU - Zhou, Ge

AU - Wang, Jiping

AU - Zhao, Mei

AU - Xie, Tong Xin

AU - Tanaka, Noriaki

AU - Sano, Daisuke

AU - Patel, Ameeta A.

AU - Ward, Alexandra M.

AU - Sandulache, Vlad C.

AU - Jasser, Samar A.

AU - Skinner, Heath D.

AU - Fitzgerald, Alison Lea

AU - Osman, Abdullah A.

AU - Wei, Yongkun

AU - Xia, Xuefeng

AU - Songyang, Zhou

AU - Mills, Gordon B.

AU - Hung, Mien Chie

AU - Caulin, Carlos

AU - Liang, Jiyong

AU - Myers, Jeffrey N.

N1 - Funding Information: We thank Drs. Guillermina Lozano and Yoko Takahashi for providing p53 −/− and p53 (R172H/H) MEFs and SKBR3, UMSCC1, HN30, and Detroit 562 stable cell lines. We also thank Drs. Kun-liang Guan, Jianhua Yang, and Xiaolu Yang for providing the plasmids. This research was supported by the University Cancer Foundation via the Institutional Research Grant program at The University of Texas MD Anderson Cancer Center to G.Z. (IRG Grant Fred 35608) and by NIH grants RO1 DE015344 to C.C.; CA133249 and GM095599 to Z.S.; and RO1 DE14613, P50CA097007, and CA016672 to J.N.M.

PY - 2014/6/19

Y1 - 2014/6/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84903627732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903627732&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2014.04.024

DO - 10.1016/j.molcel.2014.04.024

M3 - Article

C2 - 24857548

AN - SCOPUS:84903627732

SN - 1097-2765

VL - 54

SP - 960

EP - 974

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this