AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability

John D. Short, Ruhee Dere, Kevin D. Houston, Sheng Li Cai, Jinhee Kim, Judith M. Bergeron, Jianjun Shen, Jiyong Liang, Mark T. Bedford, Gordon Mills, Cheryl Lyn Walker

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The tuberous sclerosis complex 2 (Tsc2) gene product, tuberin, acts as a negative regulator of mTOR signaling, and loss of tuberin function leads to tumors of the brain, skin, kidney, heart, and lungs. Previous studies have shown that loss of tuberin function affects the stability and subcellular localization of the cyclin-dependent kinase inhibitor (CKI) p27, although the mechanism(s) by which tuberin modulates p27 stability has/have not been elucidated. Previous studies have also shown that AMP-activated protein kinase (AMPK), which functions in an energy-sensing pathway in the cell, becomes activated in the absence of tuberin. Here we show that in Tsc2-null tumors and cell lines, AMPK activation correlates with an increase in p27 levels, and inhibition of AMPK signaling decreases p27 levels in these cells. In addition, activation of AMPK led to phosphorylation of p27 at the conserved terminal threonine residue of murine p27 (T197) in both in vitro kinase assays and in cells. Phosphorylation of p27 at T197 led to increased interaction between p27 and 14-3-3 proteins and increased the protein stability of p27. Furthermore, activation of AMPK signaling promoted the interaction between p27 and 14-3-3 proteins and increased the stability of the p27 protein in a manner that was dependent on T197. These data identify a conserved mechanism for the regulation of p27 stability via phosphorylation at the terminal threonine (mT197/hT198) and binding of 14-3-3 proteins, which when AMPK is activated results in stabilization of the p27 protein.

Original languageEnglish (US)
Pages (from-to)429-439
Number of pages11
JournalMolecular Carcinogenesis
Volume49
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Fingerprint

14-3-3 Proteins
AMP-Activated Protein Kinases
Phosphorylation
Tuberous Sclerosis
Protein Stability
Threonine
Cyclin-Dependent Kinase Inhibitor p27
Null Lymphocytes
Tumor Cell Line
Brain Neoplasms
Proteins
Phosphotransferases
tuberous sclerosis complex 2 protein
Kidney
Lung
Skin
Genes

Keywords

  • 14-3-3
  • AMPK
  • Energy sensing
  • P27
  • Tsc2
  • Tuberous sclerosis complex

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Short, J. D., Dere, R., Houston, K. D., Cai, S. L., Kim, J., Bergeron, J. M., ... Walker, C. L. (2010). AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Molecular Carcinogenesis, 49(5), 429-439. https://doi.org/10.1002/mc.20613

AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. / Short, John D.; Dere, Ruhee; Houston, Kevin D.; Cai, Sheng Li; Kim, Jinhee; Bergeron, Judith M.; Shen, Jianjun; Liang, Jiyong; Bedford, Mark T.; Mills, Gordon; Walker, Cheryl Lyn.

In: Molecular Carcinogenesis, Vol. 49, No. 5, 01.05.2010, p. 429-439.

Research output: Contribution to journalArticle

Short, JD, Dere, R, Houston, KD, Cai, SL, Kim, J, Bergeron, JM, Shen, J, Liang, J, Bedford, MT, Mills, G & Walker, CL 2010, 'AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability', Molecular Carcinogenesis, vol. 49, no. 5, pp. 429-439. https://doi.org/10.1002/mc.20613
Short, John D. ; Dere, Ruhee ; Houston, Kevin D. ; Cai, Sheng Li ; Kim, Jinhee ; Bergeron, Judith M. ; Shen, Jianjun ; Liang, Jiyong ; Bedford, Mark T. ; Mills, Gordon ; Walker, Cheryl Lyn. / AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. In: Molecular Carcinogenesis. 2010 ; Vol. 49, No. 5. pp. 429-439.
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AU - Cai, Sheng Li

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AU - Bedford, Mark T.

AU - Mills, Gordon

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