Department of Cell and Molecular Biology and Microbiology and Tumor Biology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2560-5. doi: 10.1073/pnas.1320815111. Epub 2014 Feb 3.
The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a naturally occurring C-terminal fragment that accumulates in the cell nucleus. This fragment interacts with the N-terminal portion of HIF-1α spanning amino acid residues 1-390 but not with HIF-2α. In hypoxia this fragment facilitates the nuclear localization of HIF-1α, is recruited to HIF-1α target gene promoters, and enhances HIF-1α function, resulting in up-regulation of HIF-1α target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1α and potentiates angiogenesis and tumor progression.
细胞对缺氧的反应受缺氧诱导因子-1α 和 -2α（HIF-1α 和 -2α）调节。我们发现，细丝蛋白 A（FLNA），一种大型细胞骨架肌动蛋白结合蛋白，与 HIF-1α 发生物理相互作用，并促进肿瘤生长和血管生成。缺氧诱导钙蛋白酶依赖性 FLNA 裂解，生成天然存在的 C 端片段，在细胞内积累核。该片段与 HIF-1α 的 N 端部分相互作用，跨越氨基酸残基 1-390，但不与 HIF-2α 相互作用。在缺氧条件下，该片段促进 HIF-1α 的核定位，被募集到 HIF-1α 靶基因启动子，并增强 HIF-1α 的功能，导致 HIF-1α 靶基因的表达在缺氧依赖性方式上调。这些结果揭示了一种重要的机制，选择性地调节 HIF-1α 的核积累和功能，并增强血管生成和肿瘤进展。
