Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy.

Agata Desantis, Tiziana Bruno, Valeria Catena, Francesca De Nicola, Frauke Goeman, Simona Iezzi, Cristina Sorino, Maurilio Ponzoni, Gianluca Bossi, Vincenzo Federico, Francesca La Rosa, Maria Rosaria Ricciardi, Elena Lesma, Paolo D'Onorio De Meo, Tiziana Castrignanò, Maria Teresa Petrucci, Francesco Pisani, Marta Chesi, P Leif Bergsagel, Aristide Floridi, Giovanni Tonon, Claudio Passananti, Giovanni Blandino, Maurizio Fanciulli

Index: EMBO J. 34 , 1214-30, (2015)

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Abstract

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che-1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress-induced autophagy. Strikingly, Che-1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response. © 2015 Regina Elena Cancer Institute.