TSC2 Regulates VEGF Through mTOR-dependent and -Independent Pathways

Cancer Cell. 2003 Aug;4(2):147-58. doi: 10.1016/s1535-6108(03)00187-9.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Excitatory Amino Acid Transporter 2 / genetics
  • Gene Deletion
  • Gene Expression Regulation
  • Hydroxamic Acids / pharmacology
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Phosphoglycerate Kinase / genetics
  • Phosphopyruvate Hydratase / genetics
  • Protein Kinases / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Excitatory Amino Acid Transporter 2
  • Hydroxamic Acids
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • Transcription Factors
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Vascular Endothelial Growth Factor A
  • trichostatin A
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases
  • Phosphoglycerate Kinase
  • Eno1 protein, mouse
  • Phosphopyruvate Hydratase
  • Sirolimus