The TSC1 and TSC2 tumor suppressors are required for proper ER stress response and protect cells from ER stress-induced apoptosis.
Tuberous sclerosis complex (TSC)1 and TSC2 are tumor suppressors that inhibit cell growth and mutation of either gene causes benign tumors in multiple tissues. The TSC1 and TSC2 gene products form a functional complex that has GTPase-activating protein (GAP) activity toward Ras homolog enriched in brain (Rheb) to inhibit mammalian target of rapamycin complex 1 (mTORC1), which is constitutively activated in TSC mutant tumors. We found that cells with mutation in either TSC1 or TSC2 are hypersensitive to endoplasmic reticulum (ER) stress and undergo apoptosis. Although the TSC mutant cells show elevated eIF2α phosphorylation, an early ER stress response marker, at both basal and induced conditions, induction of other ER stress response markers, including ATF4, ATF6 and C/EBP homologous protein (CHOP), is severely compromised. The defects in ER stress response are restored by raptor knockdown but not by rapamycin treatment in the TSC mutant cells, indicating that a rapamycin-insensitive mTORC function is responsible for the defects in ER stress response. Consistently, activation of Rheb sensitizes cells to ER stress. Our data show an important role of TSC1/TSC2 and Rheb in unfolded protein response and cell survival. We speculate that an important physiological function of the TSC1/2 tumor suppressors is to protect cells from harmful conditions. These observations indicate a potential therapeutic application of using ER stress agents to selectively kill TSC1 or TSC2 mutant cells for TSC treatment.
Kang
Y J
YJ
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
Lu
M-K
MK
Guan
K-L
KL
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology; D046912:Multiprotein Complexes; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology
D051702:Activating Transcription Factor 6; C081452:Atf4 protein, mouse; C497112:Atf6 protein, mouse; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; C103652:Elf2 protein, mouse; D007976:Leupeptins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; 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; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde