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Chk1 is haploinsufficient for multiple functions critical to tumor suppression.

The haploinsufficient tumor suppressor Chk1 is essential for embryonic cells, but the consequences of Chk1 loss in adult tissues are unknown. Using conditional Chk1 mice, we find that proliferating mammary cells lacking Chk1 undergo apoptosis leading to developmental defects. Conditional Chk1 heterozygosity increased the number of S phase cells and caused spontaneous DNA damage. Chk1+/- epithelia also exhibit a miscoordinated cell cycle in which S phase cells display an early mitotic phenotype. These cells maintain high levels of Cdc25A, which can promote inappropriate cell cycle transitions. Thus, Chk1 heterozygosity results in three distinct haploinsufficient phenotypes that can contribute to tumorigenesis: inappropriate S phase entry, accumulation of DNA damage during replication, and failure to restrain mitotic entry.

Pubmed ID: 15261141

Authors

  • Lam MH
  • Liu Q
  • Elledge SJ
  • Rosen JM

Journal

Cancer cell

Publication Data

July 20, 2004

Associated Grants

None

Mesh Terms

  • Animals
  • Apoptosis
  • DNA Damage
  • DNA Replication
  • Epithelial Cells
  • Genes, Tumor Suppressor
  • Integrases
  • Mammary Glands, Animal
  • Mice
  • Mice, Knockout
  • Microfilament Proteins
  • Mitosis
  • Muscle Proteins
  • Phenotype
  • Protein Kinases
  • S Phase
  • Viral Proteins
  • cdc25 Phosphatases