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DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation
T Raveh1, G Droguett, M S Horwitz
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
DAP kinase is a pro-apoptotic calcium-regulated serine/threonine kinase, whose expression is frequently lost in human tumours. Here we show that DAP kinase counteracts oncogene-induced transformation by activating a p19ARF/p53-dependent apoptotic checkpoint. Ectopic expression of DAP kinase suppressed oncogenic transformation of primary embryonic fibroblasts by activating p53 in a p19ARF-dependent manner. Consequently, the fibroblasts underwent apoptosis, characterized by caspase activation and DNA fragmentation. In response to c-Myc or E2F-1, the endogenous DAP kinase protein was upregulated. Furthermore, functional or genetic inactivation of the endogenous DAP kinase reduced the extent of induction of p19ARF/p53 and weakened the subsequent apoptotic responses to c-Myc or E2F-1. These results establish a role for DAP kinase in an early apoptotic checkpoint designed to eliminate pre-malignant cells during cancer development.
Insights
Death-associated protein (DAP) kinase suppresses cancer by activating the p19ARF/p53 apoptotic pathway. Loss of DAP kinase function weakens this crucial checkpoint, allowing pre-malignant cells to survive.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Death Pathways
Background:
- DAP kinase, a calcium-regulated serine/threonine kinase, is often downregulated in human tumors.
- Loss of DAP kinase expression is linked to cancer development.
Purpose of the Study:
- To investigate the role of DAP kinase in counteracting oncogene-induced transformation.
- To elucidate the mechanism by which DAP kinase influences the p19ARF/p53 apoptotic pathway.
Main Methods:
- Ectopic expression of DAP kinase in primary embryonic fibroblasts.
- Analysis of p53 activation, caspase activation, and DNA fragmentation.
- Investigating endogenous DAP kinase levels in response to oncogenes c-Myc and E2F-1.
- Functional and genetic inactivation of DAP kinase.
Main Results:
- Ectopic DAP kinase expression suppressed oncogenic transformation by inducing p53 in a p19ARF-dependent manner.
- Fibroblasts expressing DAP kinase underwent apoptosis.
- Endogenous DAP kinase was upregulated by c-Myc and E2F-1.
- DAP kinase inactivation diminished p19ARF/p53 induction and apoptotic responses.
Conclusions:
- DAP kinase acts as a tumor suppressor by activating an early apoptotic checkpoint.
- This checkpoint eliminates pre-malignant cells through the p19ARF/p53 pathway.
- DAP kinase plays a critical role in preventing cancer development.