A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis

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.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.When DNA is damaged or when blocks to DNA replication occur, cells activate an extensive network of signaling pathways that promote cell cycle arrest and DNA repair [1]. Cell cycle arrest is mediated by checkpoints in which the activities of cyclin-dependent kinases (Cdks) are inhibited. Cell cycle arrest presumably provides time for damage to be repaired and contributes to the preservation of genomic stability and reduction of risk for diseases such as cancer. There are two well established mechanisms by which Cdks are inhibited in response to DNA damage in mammals. The first involves activation of the Cdk inhibitor p21Cip through activation of p53 [2]. The second is through inactivation of the Cdc25 family of phosphatases. The most fully understood mechanism regulating the level of a phosphatase in this family is the proteasome-mediated degradation of Cdc25A [3-5].Cdc25A phosphatase is an essential activator of cell cycle progression and its expression is tightly regulated at many levels, including transcriptional activation, reversible phosphorylation, protein-protein interaction and ubiquitin-mediated degradation [6-9]. Ubiquitin-dependent degradation of Cdc25A is a major mechanism for damage-induced S-phase checkpoint arrest. Two ubiquitin ligases, the Skp1-cullin-β-TrCP (SCFβ-TrCP) complex and the anaphase-promoting complex (APCCdh1), participate in Cdc25A turnover. The APC/C p