PMID- 25770584 OWN - NLM STAT- MEDLINE DCOM- 20150722 LR - 20211203 IS - 1460-2075 (Electronic) IS - 0261-4189 (Print) IS - 0261-4189 (Linking) VI - 34 IP - 9 DP - 2015 May 5 TI - Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy. PG - 1214-30 LID - 10.15252/embj.201489920 [doi] AB - 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. CI - (c) 2015 Regina Elena Cancer Institute. FAU - Desantis, Agata AU - Desantis A AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Bruno, Tiziana AU - Bruno T AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Catena, Valeria AU - Catena V AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. FAU - De Nicola, Francesca AU - De Nicola F AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Goeman, Frauke AU - Goeman F AD - Translational Oncogenomic Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Iezzi, Simona AU - Iezzi S AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Sorino, Cristina AU - Sorino C AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Ponzoni, Maurilio AU - Ponzoni M AD - Pathology and Myeloma Units, Molecular Oncology Division, San Raffaele Scientific Institute, Milan, Italy. FAU - Bossi, Gianluca AU - Bossi G AD - Molecular Oncogenesis Laboratory, Regina Elena National Cancer Institute, Rome, Italy. FAU - Federico, Vincenzo AU - Federico V AD - Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy. FAU - La Rosa, Francesca AU - La Rosa F AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Ricciardi, Maria Rosaria AU - Ricciardi MR AD - Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy. FAU - Lesma, Elena AU - Lesma E AD - Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy. FAU - De Meo, Paolo D'Onorio AU - De Meo PD AD - HPC CINECA, Rome, Italy. FAU - Castrignano, Tiziana AU - Castrignano T AD - HPC CINECA, Rome, Italy. FAU - Petrucci, Maria Teresa AU - Petrucci MT AD - Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy. FAU - Pisani, Francesco AU - Pisani F AD - Hematology Laboratory, Regina Elena National Cancer Institute, Rome, Italy. FAU - Chesi, Marta AU - Chesi M AD - Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ, USA. FAU - Bergsagel, P Leif AU - Bergsagel PL AD - Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ, USA. FAU - Floridi, Aristide AU - Floridi A AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Tonon, Giovanni AU - Tonon G AD - Functional Genomics of Cancer Unit, Molecular Oncology Division, San Raffaele Scientific Institute, Milan, Italy. FAU - Passananti, Claudio AU - Passananti C AD - Institute of Molecular Biology and Pathology, CNR Department of Molecular Medicine "Sapienza" University, Rome, Italy. FAU - Blandino, Giovanni AU - Blandino G AD - Translational Oncogenomic Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy. FAU - Fanciulli, Maurizio AU - Fanciulli M AD - Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy fanciulli@ifo.it. LA - eng SI - GEO/GSE45009 GR - P30 CA015083/CA/NCI NIH HHS/United States GR - P50 CA186781/CA/NCI NIH HHS/United States GR - R01 CA190045/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150314 PL - England TA - EMBO J JT - The EMBO journal JID - 8208664 RN - 0 (AATF protein, human) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (DDIT4 protein, human) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (Repressor Proteins) RN - 0 (Transcription Factors) RN - EC 2.7.1.1 (DEPTOR protein, human) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Apoptosis Regulatory Proteins/genetics/*metabolism MH - Autophagy/*physiology MH - Cell Line, Tumor MH - Cell Survival MH - Female MH - Intracellular Signaling Peptides and Proteins/genetics/metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Mice, Nude MH - Multiple Myeloma/metabolism/*pathology MH - Multiprotein Complexes/metabolism MH - Phosphorylation MH - Repressor Proteins/genetics/*metabolism MH - Stress, Physiological MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Transcription Factors/genetics/metabolism PMC - PMC4426481 OTO - NOTNLM OT - Che-1 OT - autophagy OT - mTOR OT - multiple myeloma EDAT- 2015/03/17 06:00 MHDA- 2015/07/23 06:00 PMCR- 2016/05/05 CRDT- 2015/03/16 06:00 PHST- 2014/08/27 00:00 [received] PHST- 2015/02/16 00:00 [accepted] PHST- 2015/03/16 06:00 [entrez] PHST- 2015/03/17 06:00 [pubmed] PHST- 2015/07/23 06:00 [medline] PHST- 2016/05/05 00:00 [pmc-release] AID - embj.201489920 [pii] AID - 10.15252/embj.201489920 [doi] PST - ppublish SO - EMBO J. 2015 May 5;34(9):1214-30. doi: 10.15252/embj.201489920. Epub 2015 Mar 14.