Journal
NATURE CELL BIOLOGY
Volume 9, Issue 2, Pages 218-U125Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1537
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Funding
- NCI NIH HHS [P01CA099031, P30 CA16672, CA63613, P50-CA83639, P01 CA64602] Funding Source: Medline
- NICHD NIH HHS [HD046282] Funding Source: Medline
- NIEHS NIH HHS [ES08263] Funding Source: Medline
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Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells(1,2). 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.
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