RRC ID 45831
著者 Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, Pause A.
タイトル Folliculin regulates ampk-dependent autophagy and metabolic stress survival.
ジャーナル PLoS Genet
Abstract Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function.
巻・号 10(4)
ページ e1004273
公開日 2014-4-1
DOI 10.1371/journal.pgen.1004273
PII PGENETICS-D-13-02503
PMID 24763318
PMC PMC3998892
MeSH AMP-Activated Protein Kinases / genetics* Animals Apoptosis / genetics Autophagy / genetics* Caenorhabditis elegans / genetics* Cell Line Estrone / genetics* Genes, Tumor Suppressor Mice Mice, Inbred C57BL Mutation / genetics Oxidative Stress / genetics* Signal Transduction / genetics Tumor Suppressor Proteins / genetics
IF 5.175
引用数 52
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm1944