TSC2 regulates VEGF through mTOR-dependent and -independent pathways

James B. Brugarolas, Francisca Vazquez, Archana Reddy, William R. Sellers, William G. Kaelin

Research output: Contribution to journalArticle

425 Scopus citations

Abstract

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-1α 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.

Original languageEnglish (US)
Pages (from-to)147-158
Number of pages12
JournalCancer Cell
Volume4
Issue number2
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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