TSC2 regulates VEGF through mTOR-dependent and -independent pathways.
Inactivation of the TSC2 tumor suppressor protein causes tuberous sclerosis complex (TSC), a disease characterized by highly vascular tumors. TSC2 has multiple functions including inhibition of mTOR (mammalian target of Rapamycin). We found that TSC2 regulates VEGF through mTOR-dependent and -independent pathways. TSC2 loss results in the accumulation of HIF-1alpha and increased expression of HIF-responsive genes including VEGF. Wild-type TSC2, but not a disease-associated TSC2 mutant, downregulates HIF. Rapamycin normalizes HIF levels in TSC2(-/-) cells, indicating that TSC2 regulates HIF by inhibiting mTOR. In contrast, Rapamycin only partially downregulates VEGF in this setting, implying an mTOR-independent link between TSC2 loss and VEGF. This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells.
Brugarolas
James B
JB
Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Vazquez
Francisca
F
Reddy
Archana
A
Sellers
William R
WR
Kaelin
William G
WG
D000818:Animals; D002478:Cells, Cultured; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006877:Hydroxamic Acids / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D010735:Phosphoglycerate Kinase / Q000235:genetics; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D027342:Excitatory Amino Acid Transporter 2; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C012589:trichostatin A; D011494:Protein Kinases; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D010735:Phosphoglycerate Kinase; C457379:Eno1 protein, mouse; D010751:Phosphopyruvate Hydratase; D020123:Sirolimus