TY - JOUR
T1 - TSC2 regulates VEGF through mTOR-dependent and -independent pathways
AU - Brugarolas, James B.
AU - Vazquez, Francisca
AU - Reddy, Archana
AU - Sellers, William R.
AU - Kaelin, William G.
N1 - Funding Information:
We thank H. Onda and D.J. Kwiatkowski for p53 −/− ;Tsc2 +/ + and p53 −/− ;Tsc2 −/− MEFs; J. Pouyssegur for anti-HIF-1α antibody; K. Inoki for a mutant TSC2 expression vector and sequence information on Tsc2 siRNA; J. Daley and S. Lazo-Kallanian in the FACS-Cell Sorter facility, and members of the Kaelin Laboratory for useful discussions. W.G.K. is a Howard Hughes Medical Institute Investigator. This work was supported by the NIH and by the Murray Foundation.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S1535-6108(03)00187-9
DO - 10.1016/S1535-6108(03)00187-9
M3 - Article
C2 - 12957289
AN - SCOPUS:0041920901
SN - 1535-6108
VL - 4
SP - 147
EP - 158
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -