Letter abstract
Nature Cell Biology 9, 218 - 224 (2007)
Published online: 21 January 2007 | doi:10.1038/ncb1537
The energy sensing LKB1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis
Jiyong Liang1, Shan H. Shao2,6, Zhi-Xiang Xu1, Bryan Hennessy1, Zhiyong Ding1, Michelle Larrea5, Seiji Kondo3, Dan J. Dumont2, Jordan U. Gutterman1, Cheryl L. Walker4, Joyce M. Slingerland5 & Gordon B. Mills1
Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells1, 2. 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.
- Department of Molecular Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
- Department of Medical Biophysics, University of Toronto, 2075 Bayvie Avenue, Toronto, M4N 3M5, Canada.
- Department of Neurosurgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
- Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1580 N. W. 10th Avenue, Miami, FL 33136, USA.
- Current address: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
Correspondence to: Gordon B. Mills1 gmills@mdanderson.org
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