1-beta-D-arabinofuranosylcytosine (ara-C) is the most effective agent in the treatment of acute myelogenous leukemia in man. The mechanism(s) of action of ara-C and the basis for its selectivity against leukemia cells, however, remain unclear. Incorporation of ara-C into cellular DNA is associated with inhibition of DNA synthesis and loss of clonogenic survival. The relative chain-terminating effects of the incorporated ara-C residue are sequence-dependent and result in the accumulation of DNA double-strand breaks. The finding that ara-C induces stress kinases and early response genes also provided support for the activation of a nuclear signaling cascade in the response to this agent. More recent work has demonstrated that ara-C activates a nuclear complex of the c-Abl and Lyn tyrosine kinases. Activation of the nuclear c-Abl/Lyn complex is regulated by the SHPTP1 protein tyrosine phosphatase and confers ara-C-induced signals that stabilize p53 and inhibit Cdk2. The findings also support nuclear c-Abl and Lyn as upstream effectors to induction of JNK/SAPK activity and apoptosis in the response to ara-C. The proposed work will extend these studies by defining ara-C-induced signals that function upstream to activation of the c-Abl/Lyn complex. The proposed studies will also identify effectors downstream to c-Abl and Lyn that confer ara-C-induced cell death signals from the nucleus to the cytoplasm and mitochondria.
The Specific Aims are: 1) To define ara-C-induced signals that function upstream to activation of the nuclear c-Abl/Lyn complex; 2) To study the interaction between ara-C-induced activation of the nuclear c-Abl/Lyn complex and the pro-apoptotic Rad9 checkpoint protein; 3)To define ara-C-induced pro-apoptotic signals transduced by nuclear export of c-Abl to the cytoplasm; and 4) To identify ara-C-induced cell death signals mediated by translocation of SAPK to mitochondria.
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