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1: Cancer Res. 2007 Jul 15;67(14):6605-11.
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Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice.

Ray D, Terao Y, Nimbalkar D, Hirai H, Osmundson EC, Zou X, Franks R, Christov K, Kiyokawa H.

Department of Molecular Pharmacology and Biological Chemistry, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 E. Superior Street, Chicago, IL 60611, USA.

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.

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PMID: 17638870 [PubMed - indexed for MEDLINE]