title: Hypoxia-inducible factor/MAZ-dependent induction of caveolin-1 regulates colon permeability through suppression of occludin, leading to hypoxia-induced inflammation.
abstract: Caveolae are specialized microdomains on membranes that are critical for signal transduction, cholesterol transport, and endocytosis. Caveolin-1 (CAV1) is a multifunctional protein and a major component of caveolae. Cav1 is directly activated by hypoxia-inducible factor (HIF). HIFs are heterodimers of an oxygen-sensitive α subunit, HIF1α or HIF2α, and a constitutively expressed β subunit, aryl hydrocarbon receptor nuclear translocator (ARNT). Whole-genome expression analysis demonstrated that Cav1 is highly induced in mouse models of constitutively activated HIF signaling in the intestine. Interestingly, Cav1 was increased only in the colon and not in the small intestine. Currently, the mechanism and role of HIF induction of CAV1 in the colon are unclear. In mouse models, mice that overexpressed HIF1α or HIF2α specifically in intestinal epithelial cells demonstrated an increase in Cav1 gene expression in the colon but not in the duodenum, jejunum, or ileum. HIF2α activated the Cav1 promoter in a HIF response element-independent manner. myc-associated zinc finger (MAZ) protein was essential for HIF2α activation of the Cav1 promoter. Hypoxic induction of CAV1 in the colon was essential for intestinal barrier integrity by regulating occludin expression. This may provide an additional mechanism by which chronic hypoxia can activate intestinal inflammation.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Liwei
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Nagaoka
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Hao
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA shahy@umich.edu.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D015687:Cell Hypoxia / Q000276:immunology; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007082:Ileum / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D007421:Intestine, Small / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D062793:Occludin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010539:Permeability; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D019108:Tight Junctions / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051242:Caveolin 1; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D062793:Occludin; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C495540:CAV1 protein, human; C497443:Hif1a protein, mouse; C076035:c-MYC-associated zinc finger protein; C541485:EGFR protein, mouse; C494469:VHL protein, mouse