Hemizygous Disruption of Cdc25A Inhibits Cellular Transformation and Mammary Tumorigenesis in Mice
Open Access
- 15 July 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (14) , 6605-6611
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-G2 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 G2 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-rasV12 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. [Cancer Res 2007;67(14):6605–11]Keywords
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This publication has 40 references indexed in Scilit:
- Normal Cell Cycle and Checkpoint Responses in Mice and Cells Lacking Cdc25B and Cdc25C Protein PhosphatasesMolecular and Cellular Biology, 2005
- Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and importExperimental Cell Research, 2005
- Synthesis of small molecule CDC25 phosphatases inhibitorsBioorganic & Medicinal Chemistry Letters, 2004
- Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damageNature, 2003
- SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphataseGenes & Development, 2003
- Cdc25b phosphatase is required for resumption of meiosis during oocyte maturationNature Genetics, 2002
- Absence of Apparent Phenotype in Mice Lacking Cdc25C Protein PhosphataseMolecular and Cellular Biology, 2001
- Cdc25 cell-cycle phosphatase as a target of c-mycNature, 1996
- Atm-Deficient Mice: A Paradigm of Ataxia TelangiectasiaCell, 1996
- WAF1, a potential mediator of p53 tumor suppressionCell, 1993