RESUMO
In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-alpha transcriptional activity. We found that Nur77 associates and stabilizes HIF-1alpha via indirect interaction. Nur77 was found to interact with pVHL in vivo via the alpha-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1alpha and ultimately increased the stability and transcriptional activity of HIF-1alpha. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1alpha. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-alpha. Moreover, Nur77 could not further stabilize HIF-2alpha in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-alpha by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-alpha transcriptional activity under the non- hypoxic conditions.
Assuntos
Animais , Humanos , Ratos , Proteínas de Ligação a DNA/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Modelos Biológicos , Células PC12 , Ligação Proteica , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Receptores Citoplasmáticos e Nucleares/química , Receptores de Esteroides/química , Termodinâmica , Fatores de Transcrição/química , Ativação Transcricional/genética , Ubiquitinação , Regulação para Cima/genética , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidoresRESUMO
Os receptores de estrogênio, progesterona e androgênios têm sido pesquisados e apresentam aplicaçäo prática importante com relaçäo ao tratamento de doenças hormônio-dependentes. Este artigo apresenta uma revisÒo de literatura sobre o modo de açäo, métodos de análise e valor prognóstico desses receptores hormonais em Ginecologia.