Resumen de Papel de la proteína S6K1 en el balance supervivencia/muerte celular en el hígado
Agueda González Rodríguez, Javier Alba, Angela M. Valverde
The mTOR/S6K1 signaling pathway controls proliferation and cell growth. Insulin, IGF-I, EGF are trophic factors that elicit survival effects in hepatocytes. These molecules activate mTOR/S6K1 by acting through tyrosine kinase receptors. The aim of this study was to investigate whether S6K1 deficiency alters the balance survival/cell death in hepatocytes. For this goal, we have generated immortalized hepatocyte cell lines from neonatal wild-type and S6K1-/- deficient mice. Apoptosis has been induced in these cells by activating the death receptor pathway or, alternatively, by growth factors deprivation. Our results indicate that the lack of S6K1 in hepatocytes protects from apoptosis induced by the activation of death receptors (TNFR and Fas). In fact, in S6K1-/- hepatocytes the pro-apoptotic protein Bid is down-regulated and its active proteolitic fragment is absent in response to TNF or Jo2. Moreover, neither caspase-8 is activated nor FLIP is degraded upon TNF or Jo2 treatment. In vivo, S6K1-deficient mice are protected against Concanavalin A-induced hepatic failure. Deprivation of growth factors induces apoptosis in wild-type, but not in S6K1-/- hepatocytes. This is due to the lack of the negative feed-back that increases IRS-1 serine phosphorylation and inhibits PI3-kinase/Akt and MAPK survival molecular pathways. Consequently, there is a sustained activation of Akt and MAPK in the absence of trophic factors and S6K1-deficient hepatocytes are protected from apoptosis. The molecular mechanisms by which S6K1 deficiency protects hepatocytes from apoptosis could be related with the resistance of some mTOR inhibitors in cancer therapies.
