title: Mammalian target of rapamycin complex 1 (mTORC1) enhances bortezomib-induced death in tuberous sclerosis complex (TSC)-null cells by a c-MYC-dependent induction of the unfolded protein response.
abstract: Many factors, including duration and intensity of the unfolded protein response (UPR), dictate whether cells will adapt to endoplasmic reticulum stress or undergo apoptosis. In tuberous sclerosis (TSC), elevation of mammalian target of rapamycin complex 1 (mTORC1) activity has been proposed to compound the induction of UPR transcription factors ATF4 and CHOP, suggesting that the UPR could be targeted to eradicate TSC1/2-null cells during patient therapy. Here we report that control of c-MYC translation by mTORC1 plays a key role in determining whether TSC2-null Elt3 rat leiomyoma cells apoptose in response to UPR induction by the proteasome inhibitor bortezomib. Although bortezomib induces eukaryotic initiating factor 2α phosphorylation, mTORC1 activity was also required for downstream induction of the UPR transcription factors ATF4 and CHOP by a mechanism involving increased expression of c-MYC. Although bortezomib-induced c-MYC transcription was resistant to rapamycin treatment, mTORC1 activity was required for efficient c-MYC translation. c-MYC subsequently bound to the ATF4 promoter, suggesting direct involvement of an mTORC1/c-MYC-driven signaling pathway in the activation of the UPR. Consistent with this notion, exogenously expressed c-MYC reversed the ability of rapamycin to prevent bortezomib-induced CHOP and ATF4 expression as well as apoptosis. These findings indicate that the induction of ATF4/CHOP expression occurs via mTORC1 regulation of c-MYC and that this signaling pathway is a major determinant in the ability of bortezomib to induce apoptosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202,, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Babcock
authors.forename: Hoa B
authors.initials: HB
authors.lastname: Nguyen
authors.forename: Yujun
authors.initials: Y
authors.lastname: He
authors.forename: Jeremiah W
authors.initials: JW
authors.lastname: Hendricks
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Quilliam
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C497110:Atf4 protein, rat; D001897:Boronic Acids; C497251:Ddit3 protein, rat; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624652:Tsc1 protein, rat; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000069286:Bortezomib; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: ATF4; Apoptosis; Bortezomib; Myc; Rapamycin; Tuberous Sclerosis (Tsc); Unfolded Protein Response; mTOR