Filamin-A Promotes VEGF-A Activity through the HIF-1alpha-mediated Hypoxic Response

• 作 者: XiaoweiZheng;LorenzPoellinger;LeventM.Akyürek;XianghuaZhou;TeresaPereira;MeitBj(o)rndahl;HidetakaUramoto;LakshmananGanesh;ElizabethG.Nabel;YihaiCao;JanBorén;
• 机 构: Department of Cell and Molecular Biology Karolinska Institute Stockholm Sweden
• 出 处: BIT‘s2nd Annual World Cancer Congess-2009 (2009第二届癌症大会)
• 发表日期: 2009年期

　　Hypoxia-induced angiogenesis is regulated by hypoxia-inducible factor-1 α (HIF-1α).Upon exposure to hypoxia, HIF-1α is stabilized against degradation and transloeated to the nucleus where it activates the expression of target genes, such as vascular endothelial growth factor (VEGF).In this study, we demonstrate that filamin-A (FLN-A), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α and promotes HIF-1α activity during hypoxia.In FLN-A-deficient tumor cells, hypoxia-induced nuclear translocation of HIF-1α, activation of VEGF-A expression, and secretion of VEGF-A protein were significantly reduced.Although full-length FLN-A has been shown to be predominantly distributed in the cytoplasm, we observed that a calpain-dependent and hypoxia-induced cleavage of FLN-A generated a nuclear fragment that facilitates the nuclear localization of HIF-1α and enhances HIF-1α unction.FLN-A null cells export reduced levels of VEGF-A protein, leading to decreased aetivity on endothelial cell morphology, migration and proliferation.These data suggest that FLN-A is an important regulator of HIF-1α-mediated activation of VEGF-A expression and the cellular response to hypoxia.