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Vol. 16, No. 22, pp. 2923-2934, November 15, 2002
Departments of 1 Molecular Genetics and 2 Surgical
Oncology, University of Illinois College of Medicine, Chicago, Illinois
60607, USA; 3 Department of Molecular Biology, Lerner Research
Institute, the Cleveland Clinic Foundation,
Cleveland, Ohio 44195, USA
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.
[Key Words: Cell cycle; cancer; immortalization; cyclin; Cdk; Ras; Ink4a; p21; stability; Supplemental material is available at http://www.genesdev.org.]
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