Programmed Cell Death Across the Eukaryotic Kingdoms

EU 6th Framework STREP

Research group of Adi Kimchi

DAP genes in mammalian apoptosis and cancer




Fig.: ER stress induces autophagy and caspase activation in the same cell  

The Kimchi laboratory identified a set of novel cell death promoting genes using a technical knockout approach by library antisense expression in mammalian cell cultures combined with positive growth selection. This identified the so called DAP (Death-Associated Protein) genes, one of which, DAP Ser/Thr kinase, served as a starting point for the discovery of a novel family of death-inducing kinases. This work provided a significant addition to the available molecules that regulate PCD. Current research directions include: 1). Deciphering the biochemical function of the DAPs. 2). Studying their mode of activation during apoptosis. 3) Coupling their mode(s) of action to a precise subcellular event during PCD. 4) Determining the functional position of DAP genes with respect to each other and with to other apoptotic genes such as caspases, Bcl2 family members, etc. 5) Studying the outcome of DAP-deficiency in animal model systems. 6) Studying the possible link of DAP genes to cancer in light of the concept that disruption of apoptotic checkpoint(s) is part of the multi-stage process of tumor development.

Relevant References

1) Henis-Korenblit et al. (2002) The caspase-cleaved DAP5 protein supports internal ribosome entry site-mediated translation of death proteins. Proc Natl Acad Sci USA 99, 5400-05
2) Kimchi (2001) A cell death-promoting kinase. Nature Struct Biol. 8, 824-6
3) Raveh et al., (2001) DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nature Cell Biol 3, 1-7
4) Shani et al., (2001) Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. EMBOJ 20,1099-113
5) Inbal et al., (2002) DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death.  J Cell Biol.  157 455-68


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