Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response.

ABSTRACT: The cellular response to hypoxia is regulated by hypoxia-inducible factor-1? and -2? (HIF-1? and -2?). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1? 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? spanning amino acid residues 1-390 but not with HIF-2?. In hypoxia this fragment facilitates the nuclear localization of HIF-1?, is recruited to HIF-1? target gene promoters, and enhances HIF-1? function, resulting in up-regulation of HIF-1? 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? and potentiates angiogenesis and tumor progression.

SUBMITTER: Zheng X 

PROVIDER: S-EPMC3932879 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature