Involvement of stress-activated protein kinase in the cellular response to 1-beta-D-arabinofuranosylcytosine and other DNA-damaging agents.
The cellular response to 1-beta-D-arabinofuranosylcytosine (ara-C) includes activation of Jun/AP-1, induction of c-jun transcription, and programmed cell death. The stress-activated protein (SAP) kinases stimulate the transactivation function of c-jun by amino terminal phosphorylation. The present work demonstrates that ara-C activates p54 SAP kinase. The finding that SAP kinase is also ... activated by alkylating agents (mitomycin C and cisplatinum) and the topoisomerase I inhibitor 9-amino-camptothecin supports DNA damage as an initial signal in this cascade. The results demonstrate that ara-C also induces binding of SAP kinase to the SH2/SH3-containing adapter protein Grb2. SAP kinase binds to the SH3 domains of Grb2, while interaction of the p85 alpha-subunit of phosphatidylinositol 3-kinase complex. The results also demonstrate that ara-C treatment is associated with inhibition of lipid and serine kinase activities of PI 3-kinase. The potential significance of the ara-C-induced interaction between SAP kinase and PI 3-kinase is further supported by the demonstration that Wortmannin, an inhibitor of PI 3-kinase, stimulates SAP kinase activity. The finding that Wortmannin treatment is also associated with internucleosomal DNA fragmentation may support a potential link between PI 3-kinase and regulation of both SAP kinase and programmed cell death.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Adaptor Proteins, Signal Transducing, Androstadienes, Antimetabolites, Antineoplastic, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cytarabine, DNA Damage, Enzyme Activation, Enzyme Inhibitors, GRB2 Adaptor Protein, Glutathione Transferase, Humans, JNK Mitogen-Activated Protein Kinases, Leukemia, Myeloid, Mitogen-Activated Protein Kinases, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Proteins, Proto-Oncogene Proteins c-jun, Recombinant Proteins, Stress, Physiological, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases, src Homology Domains
1-Phosphatidylinositol 3-Kinase, Adaptor Proteins, Signal Transducing, Androstadienes, Antimetabolites, Antineoplastic, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cytarabine, DNA Damage, Enzyme Activation, Enzyme Inhibitors, GRB2 Adaptor Protein, Glutathione Transferase, Humans, JNK Mitogen-Activated Protein Kinases, Leukemia, Myeloid, Mitogen-Activated Protein Kinases, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Proteins, Proto-Oncogene Proteins c-jun, Recombinant Proteins, Stress, Physiological, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases, src Homology Domains
Cell Growth Differ.
Date: Dec. 01, 1995
PubMed ID: 9019171
View in: Pubmed Google Scholar
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