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1.
Mol Cell Biol ; 33(8): 1621-31, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23401859

RESUMO

Substrate engagement by F-box proteins promotes NEDD8 modification of cullins, which is necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs). However, the mechanism by which substrate recruitment triggers cullin neddylation remains unclear. Here, we identify DCNL1 (defective in cullin neddylation 1-like 1) as a component of CRL2 called ECV (elongins BC/CUL2/VHL) and show that molecular suppression of DCNL1 attenuates CUL2 neddylation. DCNL1 via its DAD patch binds to CUL2 but is also able to bind VHL independent of CUL2 and the DAD patch. The engagement of the substrate hypoxia-inducible factor 1α (HIF1α) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. Notably, an engineered mutant form of HIF1α that associates with CUL2, but not DCNL1, fails to trigger CUL2 neddylation and retains ECV in an inactive state. These findings support a model in which substrate engagement prompts DCNL1 recruitment that facilitates the initiation of CUL2 neddylation and define DCNL1 as a "substrate sensor switch" for ECV activation.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Culina/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intracelular , Mutação , Ligação Proteica , Proteínas , Proteínas Proto-Oncogênicas , Interferência de RNA , RNA Interferente Pequeno
2.
EMBO J ; 31(11): 2448-60, 2012 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-22562152

RESUMO

Oxygen is essential for eukaryotic life and is inextricably linked to the evolution of multicellular organisms. Proper cellular response to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, is ultimately regulated by the transcription factor, hypoxia-inducible factor (HIF). Over the past decade, unprecedented molecular insight has been gained into the mammalian oxygen-sensing pathway involving the canonical oxygen-dependent prolyl-hydroxylase domain-containing enzyme (PHD)-von Hippel-Lindau tumour suppressor protein (pVHL) axis and its connection to cellular metabolism. Here we review recent notable advances in the field of hypoxia that have shaped a more complex model of HIF regulation and revealed unique roles of HIF in a diverse range of biological processes, including immunity, development and stem cell biology.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Transporte/metabolismo , Desenvolvimento Embrionário , Humanos , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Imunidade , Proteínas de Membrana/metabolismo , Camundongos , Receptores Notch/metabolismo , Proteínas Repressoras , Sirtuína 3/metabolismo , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
3.
Nat Med ; 17(7): 845-53, 2011 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-21685897

RESUMO

Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.


Assuntos
Janus Quinase 2/fisiologia , Policitemia/etiologia , Proteínas Supressoras da Sinalização de Citocina/genética , Ubiquitina-Proteína Ligases/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Animais , Modelos Animais de Doenças , Humanos , Janus Quinase 2/antagonistas & inibidores , Camundongos , Mutação/genética , Policitemia/genética , Multimerização Proteica/genética , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia
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