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1.
Proc Natl Acad Sci U S A ; 108(5): 1931-6, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21233420

RESUMO

A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.


Assuntos
Antígenos CD/fisiologia , Carcinoma de Células Renais/genética , Moléculas de Adesão Celular/fisiologia , Neoplasias Renais/genética , Proteínas de Neoplasias/fisiologia , Proteína Quinase C-delta/metabolismo , Regulação para Cima , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Antígenos CD/genética , Antígenos de Neoplasias , Moléculas de Adesão Celular/genética , Humanos , Mutação , Proteínas de Neoplasias/genética , Fosforilação , Transdução de Sinais , Proteína Supressora de Tumor Von Hippel-Lindau/genética
2.
Genes Dev ; 20(24): 3366-71, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17142669

RESUMO

Premature senescence in vitro has been attributed to oxidative stress leading to a DNA damage response. In the absence of oxidative damage that occurs at atmospheric oxygen levels, proliferation of untransformed cells continues for extended periods of time. We have investigated the role of the hypoxia-inducible factor 1alpha (HIF1alpha) transcription factor in preventing senescence in aerobic and hypoxic conditions. Using embryonic fibroblasts from a conditional HIF1alpha knockout mouse, we found that loss of HIF1alpha under aerobic conditions significantly accelerated the onset of cellular senescence, and decreased proliferation under hypoxia. Furthermore, we identify the macrophage migration inhibitory factor (MIF) as a crucial effector of HIF1alpha that delays senescence. Inhibition of MIF phenocopies loss of HIF1alpha. Our findings highlight a novel role for HIF1alpha under aerobic conditions, and identify MIF as a target responsible for this function.


Assuntos
Senescência Celular/fisiologia , Fibroblastos/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/fisiologia , Aerobiose , Animais , Hipóxia Celular , Fibroblastos/efeitos da radiação , Raios gama , Regulação da Expressão Gênica , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos , Camundongos Knockout , Transcrição Gênica
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