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 B. Mills

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    633 Scopus citations

    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 2007

    ASJC Scopus subject areas

    • Cell Biology

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  • Cite this

    Liang, J., Shao, S. H., Xu, Z. X., Hennessy, B., Ding, Z., Larrea, M., Kondo, S., Dumont, D. J., Gutterman, J. U., Walker, C. L., Slingerland, J. M., & Mills, G. B. (2007). The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nature Cell Biology, 9(2), 218-224. https://doi.org/10.1038/ncb1537