Abstract
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(2) 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 Cdc25A-null mouse strain we recently generated. Whereas Cdc25A(-/-) mice exhibit early embryonic lethality, Cdc25A(+/-) mice show no appreciable developmental defect. Cdc25A(+/-) mouse embryonic fibroblasts (MEF) exhibit normal kinetics of cell cycle progression at early passages, modestly enhanced G(2) checkpoint response to DNA damage, and shortened proliferative life span, compared with wild-type MEFs. Importantly, Cdc25A(+/-) MEFs are significantly resistant to malignant transformation induced by coexpression of H-ras(V12) 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, Cdc25A(+/-) mice show substantially prolonged latency in mammary tumorigenesis induced by MMTV-H-ras or MMTV-neu transgene, whereas MMTV-myc-induced tumorigenesis is not significantly affected by Cdc25A heterozygosity. Mammary tissues of Cdc25A(+/-);MMTV-neu 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 Cdc25A plays a rate-limiting role in transformation and tumor initiation mediated by ras activation.
Highlights
Cyclin-dependent kinases (CDK) play central roles in promoting progression of the cell cycle in all eukaryotic cells [1]
The present study has shown that hemizygous disruption of the Cdc25A gene results in inhibition of ras-mediated transformation, continuous cell cycle progression and serum-induced cell cycle entry are minimally affected
Tumorigenesis induced by the MMTV-Hras or neu transgene is substantially delayed in Cdc25A+/À mice
Summary
Cyclin-dependent kinases (CDK) play central roles in promoting progression of the cell cycle in all eukaryotic cells [1]. CDK activity undergoes multiple layers of regulatory processes, including. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Terao: Department of Obstetrics and Gynecology, Juntendo University, Tokyo 113-8421, Japan. Zou: Department of Pathology, Ohio State University, Columbus, OH 43221
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