Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence

Xianghong Zou, Dipankar Ray, Aileen Aziyu, Konstantin Christov, Alexander D. Boiko, Andrei V. Gudkov, Hiroaki Kiyokawa*

*Corresponding author for this work

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2923-2934
Number of pages12
JournalGenes and Development
Volume16
Issue number22
DOIs
StatePublished - Nov 15 2002

Keywords

  • Cancer
  • Cdk
  • Cell cycle
  • Cyclin
  • Immortalization
  • Ink4a
  • P21
  • Ras
  • Stability

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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