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Proc Natl Acad Sci U S A ; 99(16): 10423-8, 2002 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-12149454

RESUMO

Hypoxia-inducible factor-1 (HIF) is a transcription factor central to oxygen homeostasis. It is regulated via its alpha isoforms. In normoxia they are ubiquitinated by the von Hippel-Lindau E3 ligase complex and destroyed by the proteasome, thereby preventing the formation of an active transcriptional complex. Oxygen-dependent enzymatic hydroxylation of either of two critical prolyl residues in each HIFalpha chain has recently been identified as the modification necessary for targeting by the von Hippel-Lindau E3 ligase complex. Here we demonstrate that polypeptides bearing either of these prolyl residues interfere with the degradative pathway, resulting in stabilization of endogenous HIFalpha chains and consequent up-regulation of HIF target genes. Similar peptides in which the prolyl residues are mutated are inactive. Induction of peptide expression in cell cultures affects physiologically important functions such as glucose transport and leads cocultured endothelial cells to form tubules. Coupling of these HIFalpha sequences to the HIV tat translocation domain allows delivery of recombinant peptide to cells with resultant induction of HIF-dependent genes. Injection of tat-HIF polypeptides in a murine sponge angiogenesis assay causes a markedly accelerated local angiogenic response and induction of glucose transporter-1 gene expression. These results demonstrate the feasibility of using these polypeptides to enhance HIF activity, opening additional therapeutic avenues for ischemic diseases.


Assuntos
Neovascularização Fisiológica/fisiologia , Peptídeos/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Animais , Sítios de Ligação , Linhagem Celular , Endotélio Vascular , Feminino , Expressão Gênica , Produtos do Gene tat/genética , Genes Reporter , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Ligases , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/genética , RNA Mensageiro , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/genética , Proteína Supressora de Tumor Von Hippel-Lindau
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