title: The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis.
abstract: Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells. We present evidence that the cyclin-dependent kinase inhibitor p27(Kip1), 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 (p27(T198A)) 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.
authors.affiliation: Department of Molecular Therapeutics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Liang
authors.forename: Shan H
authors.initials: SH
authors.lastname: Shao
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Xu
authors.forename: Bryan
authors.initials: B
authors.lastname: Hennessy
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ding
authors.forename: Michelle
authors.initials: M
authors.lastname: Larrea
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Dumont
authors.forename: Jordan U
authors.initials: JU
authors.lastname: Gutterman
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Slingerland
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004734:Energy Metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D009097:Multienzyme Complexes; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases