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-1a and -2a (HIF-1a and -2a). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1a 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-1a spanning amino acid residues 1-390 but not with HIF-2a. In hypoxia this fragment facilitates the nuclear localization of HIF-1a, is recruited to HIF-1a target gene promoters, and enhances HIF-1a function, resulting in up-regulation of HIF-1a target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1a and potentiates angiogenesis and tumor progression.