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 selectivity against leukemic cells, however, remains unclear. The incorporation of ara-C into leukemia cell DNA correlates 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 fragments. Other studies have demonstrated that ara-C induces a pattern of internucleosomal DNA fragmentation observed during apoptosis. The cellular response to ara-C includes transcriptional activation of c-jun and other early response genes. Ara-C-induced c-jun transcription is mediated by binding of activated Jun/AP-1 to the c-jun promoter. Ara-C activates a nuclear cascade involving the c-Abl protein tyrosine kinase. c-Abl acts upstream to the stress activated protein (SAP, JNK) kinase which phosphorylates Jun/AP-1 and induces c-jun transcription. The proposed work will extend our studies on ara-C-induced apoptosis is associated with proteolytic activation of the c-Abl-more SAP kinase cascade and the role of these signals in regulating the cellular response to ara-C. Our hypothesis is that this pathway contributes to our recent finding that ara-C induced apoptosis is associated with proteolytic activation of protein kinase C (PKC) delta. The cleaved form of PKC delta may be responsible in part for induction of apoptosis. The findings obtained in the proposed work with ara-C should represent a paradigm for studies on the cellular response to other DNA-damaging agents.
The Specific Aims are: 1) To define the mechanisms responsible for ara-C induced activation of SAP kinase. 2) to study the role of the protein tyrosine phosphatase SHPTP1 in ara-C-induced activation of c-Abl and SAP kinase. 3) To determine the effects of ara-C-induced c-Abl and SAP kinase signaling on the regulation of cyclin function. 4) To define the relationship between ara-C-induced signaling, proteolytic activation of PKC delta and apoptosis.
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