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| TSC2 regulates VEGF through mTOR-dependent and -independent pathways |
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| Author(s): Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG |
| Source: CANCER CELL Volume: 4 Issue: 2 Pages: 147-158 Published: AUG 2003 |
| Times Cited: 174 References: 87 |
| 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 Hill 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Kaelin, WG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA |
Addresses:
1. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
2. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA
3. Howard Hughes Med Inst, Boston, MA 02115 USA |
| Publisher: CELL PRESS, 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA |
| Subject Category: Oncology |
| IDS Number: 716ZH |
| ISSN: 1535-6108 |
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