Hemizygous Disruption of Cdc25a Inhibits Cellular Transformation and Mammary Tumorigenesis in Mice.
From: Department of Molecular Pharmacology and Biological Chemistry, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 E. Superior Street, Chicago, IL 60611, USA.
Cancer research
- Publish Date: Jul 2007
- ISSN: 0008-5472
- Volume: 67
- Issue: 14
- Pages: 6605-11
- Medium: Print
- Language: English
- Citation (JAMA): Ray Dipankar, Terao Yasuhisa, Nimbalkar Dipali, et al. Hemizygous Disruption of Cdc25a Inhibits Cellular Transformation and Mammary Tumorigenesis in Mice.. Cancer Res. Jul 2007;67:6605-11
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.
Mesh Headings (Keywords): Animals, Cell Cycle, Cell Transformation, Neoplastic, Cells, Cultured, Fibroblasts, G2 Phase, Gene Expression Regulation, Neoplastic, Mammary Neoplasms, Animal, Mice, Mice, Inbred C57BL, Mice, Transgenic, S Phase, Time Factors, cdc25 Phosphatases, ras Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 17638870
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