Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response
Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response
复制标题
DOI：
10.1073/pnas.1320815111
复制
发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Poellinger, Lorenz
中科院分区：
文献类型：
--
作者：
Zheng, Xiaowei;Zhou, Alex-Xianghua;Poellinger, Lorenz
细胞对缺氧的反应由缺氧诱导因子-1 α和-2 α（HIF-1 α和-2 α）调节。我们已经发现细丝蛋白A（FLNA），一种大的细胞骨架肌动蛋白结合蛋白，与HIF-1 α物理相互作用，促进肿瘤生长和血管生成。缺氧诱导FLNA的钙蛋白酶依赖性切割，以产生在细胞核中积累的天然存在的C-末端片段。该片段与跨越氨基酸残基1-390的HIF-1 α的N末端部分相互作用，但不与HIF-2 α相互作用。在缺氧时，该片段促进HIF-1 α的核定位，被募集到HIF-1 α靶基因启动子，并增强HIF-1 α功能，导致HIF-1 α靶基因表达以缺氧依赖性方式上调。这些结果揭示了选择性调节HIF-1 α的核积累和功能并增强血管生成和肿瘤进展的重要机制。
The cellular response to hypoxia is regulated by hypoxia-inducible factor-1 alpha and -2 alpha (HIF-1 alpha and -2 alpha). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1 alpha 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-1 alpha spanning amino acid residues 1-390 but not with HIF-2 alpha. In hypoxia this fragment facilitates the nuclear localization of HIF-1 alpha, is recruited to HIF-1 alpha target gene promoters, and enhances HIF-1 alpha function, resulting in up-regulation of HIF-1 alpha target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1 alpha and potentiates angiogenesis and tumor progression.