title: Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy.
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.
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Desantis
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bruno
authors.affiliation: 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.
authors.forename: Valeria
authors.initials: V
authors.lastname: Catena
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Nicola
authors.affiliation: Translational Oncogenomic Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Frauke
authors.initials: F
authors.lastname: Goeman
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Iezzi
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sorino
authors.affiliation: Pathology and Myeloma Units, Molecular Oncology Division, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Molecular Oncogenesis Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bossi
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Federico
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: La Rosa
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lesma
authors.affiliation: HPC CINECA, Rome, Italy.
authors.forename: Paolo D'Onorio
authors.initials: PD
authors.lastname: De Meo
authors.affiliation: HPC CINECA, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Castrignanò
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Hematology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ, USA.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Aristide
authors.initials: A
authors.lastname: Floridi
authors.affiliation: Functional Genomics of Cancer Unit, Molecular Oncology Division, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Institute of Molecular Biology and Pathology, CNR Department of Molecular Medicine "Sapienza" University, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Passananti
authors.affiliation: Translational Oncogenomic Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.affiliation: Epigenetics Laboratory, Molecular Medicine Area Regina Elena National Cancer Institute, Rome, Italy fanciulli@ifo.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fanciulli
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; C469991:DDIT4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D012097:Repressor Proteins; D014157:Transcription Factors; C556139:DEPTOR protein, human; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Che‐1; autophagy; mTOR; multiple myeloma