Tuberin activates the proapoptotic molecule BAD.
TSC1, encoding hamartin, and TSC2, encoding tuberin, are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis (TSC). TSC affects approximately 1 in 6000 individuals and is characterized by the development of tumors, named hamartomas, in different organs. Hamartin and tuberin form a complex, of which tuberin is assumed to be the functional component. The TSC proteins have been implicated in the control of cell cycle and cell size. In addition to enhanced growth, reduced death rates can lead to tumor development. Therefore, defects in the apoptosis-inducing pathways contribute to neoplastic cell expansion. Here, we show that tuberin triggers apoptosis, accompanied by downregulation of p70S6K activity and of phosphorylation of BAD on residue Ser136, and by upregulation of the interaction of BAD/BCL-2 and BAD/BCL-XL. AKT phosphorylation negatively regulates tuberin's potential to trigger apoptosis. Experiments with BAD-/- cells demonstrate BAD to be a mediator of tuberin's effects on the regulation of apoptosis. Tuberin interferes with insulin-like growth factor-1-induced BAD Ser136 phosphorylation and cell survival. Our work proposes a model in which tuberin-mediated inhibition of p70S6K activates BAD to heterodimerize with BCL-2 and BCL-XL to promote apoptosis. A mutation of TSC2--as it occurs in TSC patients--attenuates this proapoptotic potential, underscoring the relevance of our findings for human pathophysiology.
Freilinger
A
A
Medical Genetics, Obstetrics and Gynecology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria.
Rosner
M
M
Krupitza
G
G
Nishino
M
M
Lubec
G
G
Korsmeyer
S J
SJ
Hengstschläger
M
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D004273:DNA, Neoplasm / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D006367:HeLa Cells / Q000166:cytology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases; D014162:Transfection / Q000379:methods; D014402:Tuberous Sclerosis / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D002843:Chromatin; D004273:DNA, Neoplasm; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051025:bcl-Associated Death Protein; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases