Brugarolas James B, Vazquez Francisca, Reddy Archana, Sellers William R, Kaelin William G
Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Cancer Cell. 2003 Aug;4(2):147-58. doi: 10.1016/s1535-6108(03)00187-9.
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.
TSC2肿瘤抑制蛋白的失活会导致结节性硬化症（TSC），这是一种以高度血管化肿瘤为特征的疾病。TSC2具有多种功能，包括抑制mTOR（雷帕霉素的哺乳动物靶点）。我们发现TSC2通过mTOR依赖和非依赖途径调节VEGF。TSC2缺失导致HIF-1α积累，并增加包括VEGF在内的HIF反应基因的表达。野生型TSC2而非与疾病相关的TSC2突变体可下调HIF。雷帕霉素使TSC2（-/-）细胞中的HIF水平正常化，表明TSC2通过抑制mTOR调节HIF。相比之下，在这种情况下雷帕霉素仅部分下调VEGF，这意味着TSC2缺失与VEGF之间存在mTOR非依赖的联系。该途径可能涉及染色质重塑，因为HDAC抑制剂曲古抑菌素A可下调TSC2（-/-）细胞中的VEGF。
