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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 1 (ET)
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Johnson, George S
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Dana-Farber Cancer Institute
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Kawano, Takeshi; Ito, Masaki; Raina, Deepak et al. (2007) MUC1 oncoprotein regulates Bcr-Abl stability and pathogenesis in chronic myelogenous leukemia cells. Cancer Res 67:11576-84
Wei, Xiaolong; Xu, Hai; Kufe, Donald (2007) Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res 67:1853-8
Raina, Deepak; Ahmad, Rehan; Kumar, Shailendra et al. (2006) MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. EMBO J 25:3774-83
Wei, Xiaolong; Xu, Hai; Kufe, Donald (2005) Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell 7:167-78
Yoshida, Kiyotsugu; Yamaguchi, Tomoko; Natsume, Tohru et al. (2005) JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol 7:278-85
Agata, Naoki; Nogi, Hiroko; Bamberg, Michael et al. (2005) The angiogenesis inhibitor NM-3 is active against human NSCLC xenografts alone and in combination with docetaxel. Cancer Chemother Pharmacol 56:610-4
Raina, Deepak; Pandey, Pramod; Ahmad, Rehan et al. (2005) c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem 280:11147-51
Huang, Lei; Chen, Dongshu; Liu, Derek et al. (2005) MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res 65:10413-22
Raina, Deepak; Kharbanda, Surender; Kufe, Donald (2004) The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J Biol Chem 279:20607-12
Li, Quan; Ren, Jian; Kufe, Donald (2004) Interaction of human MUC1 and beta-catenin is regulated by Lck and ZAP-70 in activated Jurkat T cells. Biochem Biophys Res Commun 315:471-6

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