Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence
AUTOR(ES)
Zou, Xianghong
FONTE
Cold Spring Harbor Laboratory Press
RESUMO
A large number of human cancers display alterations in the Ink4a/cyclin D/Cdk4 genetic pathway, suggesting that activation of Cdk4 plays an important role in oncogenesis. Here we report that Cdk4-null mouse embryonic fibroblasts are resistant to transformation in response to Ras activation with dominant-negative (DN) p53 expression or in the Ink4a/Arf-null background, judged by foci formation, anchorage-independent growth, and tumorigenesis in athymic mice. Cdk4-null fibroblasts proliferate at normal rates during early passages. Whereas Cdk4+/+Ink4a/Arf−/− cells are immortal in culture, Cdk4−/−Ink4a/Arf−/− cells undergo senescence during continuous culture, as do wild-type cells. Activated Ras also induces premature senescence in Cdk4−/−Ink4a/Arf−/− cells and Cdk4−/− cells with DNp53 expression. Thus, Cdk4 deficiency causes senescence in a unique Arf/p53-independent manner, which accounts for the loss of transformation potential. Cdk4-null cells express high levels of p21Cip1/Waf1 with increased protein stability. Suppression of p21Cip1/Waf1 by small interfering RNA (siRNA), as well as expression of HPV-E7 oncoprotein, restores immortalization and Ras-mediated transformation in Cdk4−/−Ink4a/Arf−/− cells and Cdk4−/− cells with DNp53 expression. Therefore, Cdk4 is essential for immortalization, and suppression of Cdk4 could be a prospective strategy to recruit cells with inactive Arf/p53 pathway to senescence.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=187486Documentos Relacionados
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