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

Abstract

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.

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Figure 1: Phosphorylation of p27 at Thr 198 in vivo and p27 stability.
Figure 2: p27 Thr 198 phosphorylation regulates cell cycle and and macroautophagy.
Figure 3: p27 siRNA inhibits cell viability in response to autophagy stimuli.
Figure 4: LKB1–AMPK pathway regulates p27 protein abundance and Thr 198 phosphorylation.
Figure 5: p27 is required for AMPK-induced autophagy and cell survival.

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Acknowledgements

J.L. is supported by the Odyssey Program of the Cockrell Foundation Award for Scientific Achievement from MD Anderson Cancer Center. We thank K. W. Cheng for help with statistical analysis, Y. Lu and Q. Yu for help with RPPA microarray, the MD Anderson Cancer Center Breast Tumor Bank for providing samples, and K. Donner Jr. for electron microscopy, and M.-C. Hung, S.-Y. Lin, F. X. Claret and J. R. Woodgett for helpful discussion. This work is supported by National Institutes of Health SPORE (P50-CA83639) and PO1 CA64602, PO1CA099031, CCSG grant P30 CA16672, and DAMD (17-02-01-0694) to G.B.M. and National Cancer Institue (CA63613), National Institute of Environmental Health Sciences (ES08263) and National Institute of Child Health and Human Development (HD046282) to C.L.W.

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Correspondence to Gordon B. Mills.

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Liang, J., Shao, S., Xu, ZX. et al. The energy sensing LKB1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9, 218–224 (2007). https://doi.org/10.1038/ncb1537

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