title: Identification of Pur alpha as a new hypoxia response factor responsible for coordinated induction of the beta 2 integrin family.
abstract: Central to the process of inflammation are hypoxic conditions that lead to the binding of circulating leukocytes to the endothelium. We have previously shown that such binding is mediated by monocytes being able to directly sense hypoxic conditions and respond by inducing their surface expression of the beta(2) integrin family of adhesion molecules. In this study, we show that coordinated induction of the beta(2) integrins during direct hypoxia-sensing occurs through transcriptional activation of each of the genes by which they are encoded. Certain of the molecular mechanisms that mediate this activation in transcription are dependent upon hypoxia-inducible factor-1 (HIF-1), whereas others are HIF-1 independent. In search of these HIF-1-independent mechanisms, we identified Pur alpha as a new hypoxia-response factor. Binding of Pur alpha to the HIF-1-independent beta(2) integrin promoters is induced by hypoxia and mutagenesis of these Pur alpha-binding sites almost completely abolishes the ability of the promoters to respond to hypoxic conditions. Additional studies using siRNA directed against Pur alpha also revealed a loss in the hypoxic response of the beta(2) integrin promoters. Taken together, our findings demonstrate that hypoxia induces a coordinated up-regulation in beta(2) integrin expression that is dependent upon transcriptional mechanisms mediated by HIF-1 and Pur alpha.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Kong
authors.forename: Melanie
authors.initials: M
authors.lastname: Scully
authors.forename: C Simon
authors.initials: CS
authors.lastname: Shelley
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D018845:CD11 Antigens / Q000096:biosynthesis / Q000235:genetics; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D039521:CD11c Antigen / Q000096:biosynthesis / Q000235:genetics; D018821:CD18 Antigens / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020298:U937 Cells; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D018845:CD11 Antigens; D039481:CD11b Antigen; D039521:CD11c Antigen; D018821:CD18 Antigens; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D008565:Membrane Proteins; C501130:PURA protein, human; D012333:RNA, Messenger; D014157:Transcription Factors