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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cells, Cultured
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Excitatory Amino Acid Transporter 2 / genetics
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Gene Deletion
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Gene Expression Regulation
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Hydroxamic Acids / pharmacology
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Hypoxia / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Phosphoglycerate Kinase / genetics
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Phosphopyruvate Hydratase / genetics
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Protein Kinases / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Ribosomal Protein S6 Kinases / metabolism
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Transcription Factors / metabolism
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Transcription, Genetic
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
Substances
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Excitatory Amino Acid Transporter 2
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Hydroxamic Acids
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Hypoxia-Inducible Factor 1, alpha Subunit
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Repressor Proteins
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Transcription Factors
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Vascular Endothelial Growth Factor A
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trichostatin A
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Protein Kinases
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mTOR protein, mouse
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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Phosphoglycerate Kinase
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Eno1 protein, mouse
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Phosphopyruvate Hydratase
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Sirolimus