The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis

Jiyong Liang, Shan H. Shao, Zhi Xiang Xu, Bryan Hennessy, Zhiyong Ding, Michelle Larrea, Seiji Kondo, Dan J. Dumont, Jordan U. Gutterman, Cheryl L. Walker, Joyce M. Slingerland, Gordon Mills

Research output: Contribution to journalArticle

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Abstract

Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells. We present evidence that the cyclin-dependent kinase inhibitor p27Kip1, is phosphorylated at Thr 198 downstream of the Peutz-Jeghers syndrome protein-AMP-activated protein kinase (LKB1-AMPK) energy-sensing pathway, thereby increasing p27 stability and directly linking sensing of nutrient concentration and bioenergetics to cell-cycle progression. Ectopic expression of wild-type and phosphomimetic Thr 198 to Asp 198 (T198D), but not unstable Thr 198 to Ala 198 (p27T198A) is sufficient to induce autophagy. Under stress conditions that activate the LKB1-AMPK pathway with subsequent induction of autophagy, p27 knockdown results in apoptosis. Thus LKB1-AMPK pathway-dependent phosphorylation of p27 at Thr 198 stabilizes p27 and permits cells to survive growth factor withdrawal and metabolic stress through autophagy. This may contribute to tumour-cell survival under conditions of growth factor deprivation, disrupted nutrient and energy metabolism, or during stress of chemotherapy.

Original languageEnglish (US)
Pages (from-to)218-224
Number of pages7
JournalNature Cell Biology
Volume9
Issue number2
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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AMP-Activated Protein Kinases
Autophagy
Phosphorylation
Apoptosis
Energy Metabolism
Food
Cell Survival
Intercellular Signaling Peptides and Proteins
Peutz-Jeghers Syndrome
Physiological Stress
Cyclin-Dependent Kinases
Cell Cycle
Drug Therapy
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. / Liang, Jiyong; Shao, Shan H.; Xu, Zhi Xiang; Hennessy, Bryan; Ding, Zhiyong; Larrea, Michelle; Kondo, Seiji; Dumont, Dan J.; Gutterman, Jordan U.; Walker, Cheryl L.; Slingerland, Joyce M.; Mills, Gordon.

In: Nature Cell Biology, Vol. 9, No. 2, 01.02.2007, p. 218-224.

Research output: Contribution to journalArticle

Liang, J, Shao, SH, Xu, ZX, Hennessy, B, Ding, Z, Larrea, M, Kondo, S, Dumont, DJ, Gutterman, JU, Walker, CL, Slingerland, JM & Mills, G 2007, 'The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis', Nature Cell Biology, vol. 9, no. 2, pp. 218-224. https://doi.org/10.1038/ncb1537
Liang, Jiyong ; Shao, Shan H. ; Xu, Zhi Xiang ; Hennessy, Bryan ; Ding, Zhiyong ; Larrea, Michelle ; Kondo, Seiji ; Dumont, Dan J. ; Gutterman, Jordan U. ; Walker, Cheryl L. ; Slingerland, Joyce M. ; Mills, Gordon. / The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. In: Nature Cell Biology. 2007 ; Vol. 9, No. 2. pp. 218-224.
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