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Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice.

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.

Pubmed ID: 17638870


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


Cancer research

Publication Data

July 15, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA 112282
  • Agency: NICHD NIH HHS, Id: HD 38085
  • Agency: NCI NIH HHS, Id: R01 CA 100204
  • Agency: NICHD NIH HHS, Id: U54 HD 40093

Mesh Terms

  • 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