title: Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells.
abstract: Overexpression of Rho kinase 1 (ROCK1) and the G protein RhoA is implicated in breast cancer progression, but oncogenic mutations are rare, and the molecular mechanisms that underlie increased ROCK1 and RhoA expression have not been determined. RhoA-bound ROCK1 phosphorylates myosin light chain (MLC), which is required for actin-myosin contractility. RhoA also activates focal adhesion kinase (FAK) signaling. Together, these pathways are critical determinants of the motile and invasive phenotype of cancer cells. We report that hypoxia-inducible factors coordinately activate RhoA and ROCK1 expression and signaling in breast cancer cells, leading to cell and matrix contraction, focal adhesion formation, and motility through phosphorylation of MLC and FAK. Thus, intratumoral hypoxia acts as an oncogenic stimulus by triggering hypoxia-inducible factor → RhoA → ROCK1 → MLC → FAK signaling in breast cancer cells.
authors: Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Departments of Pediatrics, Oncology, Medicine, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors: Daniele M
authors: DM
authors: Gilkes
authors: Lisha
authors: L
authors: Xiang
authors: Sun Joo
authors: SJ
authors: Lee
authors: Pallavi
authors: P
authors: Chaturvedi
authors: Maimon E
authors: ME
authors: Hubbi
authors: Denis
authors: D
authors: Wirtz
authors: Gregg L
authors: GL
authors: Semenza
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003094:Collagen / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D059016:Tumor Microenvironment; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003094:Collagen; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D010100:Oxygen
keywords: cytoskeletal reprogramming; metastasis; migration; oxygen; tumor microenvironment