title: A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis.
abstract: BACKGROUND
  Failure to regulate the levels of Cdc25A phosphatase during the cell cycle or during a checkpoint response causes bypass of DNA damage and replication checkpoints resulting in genomic instability and cancer. During G1 and S and in cellular response to DNA damage, Cdc25A is targeted for degradation through the Skp1-cullin-β-TrCP (SCFβ-TrCP) complex. This complex binds to the Cdc25A DSG motif which contains serine residues at positions 82 and 88. Phosphorylation of one or both residues is necessary for the binding and degradation to occur.
  
  
  RESULTS
  We now show that mutation of serine 88 to phenylalanine, which is a cancer-predisposing polymorphic variant in humans, leads to early embryonic lethality in mice. The mutant protein retains its phosphatase activity both in vitro and in cultured cells. It fails to interact with the apoptosis signal-regulating kinase 1 (ASK1), however, and therefore does not suppress ASK1-mediated apoptosis.
  
  
  CONCLUSIONS
  These data suggest that the DSG motif, in addition to its function in Cdc25A-mediated degradation, plays a role in cell survival during early embyogenesis through suppression of ASK1-mediated apoptosis.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. peter.stambrook@uc.edu.
authors.forename: El Mustapha
authors.initials: el M
authors.lastname: Bahassi
authors.forename: Moying
authors.initials: M
authors.lastname: Yin
authors.forename: Susan B
authors.initials: SB
authors.lastname: Robbins
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Li
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Conrady
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Rhett A
authors.initials: RA
authors.lastname: Kovall
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Herr
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook