title: 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-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.
authors.affiliation: Department of Cell and Molecular Biology and Microbiology and Tumor Biology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zheng
authors.forename: Alex-Xianghua
authors.initials: AX
authors.lastname: Zhou
authors.forename: Pegah
authors.initials: P
authors.lastname: Rouhi
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.forename: Teresa
authors.initials: T
authors.lastname: Pereira
authors.forename: Levent M
authors.initials: LM
authors.lastname: Akyürek
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D064448:Filamins / Q000378:metabolism*; D005453:Fluorescence; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D064593:Heterografts; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D064448:Filamins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: cancer; signal transduction; subcellular localization