Abstract

<div>Abstract<p>CDC25A phosphatase activates multiple cyclin-dependent kinases (CDK) during cell cycle progression. Inactivation of CDC25A by ubiquitin-mediated degradation is a major mechanism of DNA damage-induced S-G<sub>2</sub> checkpoint. Although increased CDC25A expression has been reported in various human cancer tissues, it remains unclear whether CDC25A activation is a critical rate-limiting step of carcinogenesis. To assess the role for CDC25A in cell cycle control and carcinogenesis, we used a <i>Cdc25A</i>-null mouse strain we recently generated. Whereas <i>Cdc25A</i><sup>−/−</sup> mice exhibit early embryonic lethality, <i>Cdc25A</i><sup>+/−</sup> mice show no appreciable developmental defect. <i>Cdc25A</i><sup>+/−</sup> mouse embryonic fibroblasts (MEF) exhibit normal kinetics of cell cycle progression at early passages, modestly enhanced G<sub>2</sub> checkpoint response to DNA damage, and shortened proliferative life span, compared with wild-type MEFs. Importantly, <i>Cdc25A</i><sup>+/−</sup> MEFs are significantly resistant to malignant transformation induced by coexpression of <i>H-ras</i><sup>V12</sup> and a dominant negative p53 mutant. The rate-limiting role for CDC25A in transformation is further supported by decreased transformation efficiency in MCF-10A human mammary epithelial cells stably expressing CDC25A small interfering RNA. Consistently, <i>Cdc25A</i><sup>+/−</sup> mice show substantially prolonged latency in mammary tumorigenesis induced by MMTV-<i>H-ras</i> or MMTV-<i>neu</i> transgene, whereas MMTV-<i>myc</i>–induced tumorigenesis is not significantly affected by <i>Cdc25A</i> heterozygosity. Mammary tissues of <i>Cdc25A</i><sup>+/−</sup>;MMTV-<i>neu</i> mice before tumor development display less proliferative response to the oncogene with increased tyrosine phosphorylation of CDK1/2, but show no significant change in apoptosis. These results suggest that <i>Cdc25A</i> plays a rate-limiting role in transformation and tumor initiation mediated by <i>ras</i> activation. [Cancer Res 2007;67(14):6605–11]</p></div>

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