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Cancer Cell. 2003 Aug;4(2):147-58.

TSC2 regulates VEGF through mTOR-dependent and -independent pathways.

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Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.


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.

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