DAP kinase activates a p19(ARF)/p53-mediated apoptotic checkpoint to suppress oncogenic transformation

DAP kinase is a pro-apoptotic calcium-regulated serine/threonine kinase, wh ose expression is frequently lost in human tumours, Here we show that DAP k inase counteracts oncogene-induced transformation by activating a p19(ARF)/ p53-dependent apoptotic checkpoint. Ectopic expression of DAP kinase suppre ssed oncogenic transformation of primary embryonic fibroblasts by activatin g p53 in a p19(ARF)-dependent manner. Consequently, the fibroblasts underwe nt apoptosis, characterized by caspase activation and DNA fragmentation. In response to c-Myc or E2F-1, the endogenous DAP kinase protein was upregula ted. Furthermore, functional or genetic inactivation of the endogenous DAP kinase reduced the extent of induction of p19(ARF)/p53 and weakened the sub sequent apoptotic responses to c-Myc or E2F-1. These results establish a ro le for DAP kinase in an early apoptotic checkpoint designed to eliminate pr e-malignant cells during cancer development.