The goal of these studies is to determine the role of activation of c-Jun by N-terminal phosphorylation in autocrine-driven tumors. During the previous funding period, the investigators have shown that 1) the transcription factor EGR-1 is a potent suppressor of PDGF-B transformed NIH-3T3 cells, 2) activation of c-Jun in certain human tumor lines is associated with constitutively active c-Jun N-terminal kinase, and human PC3 prostate carcinoma cells which express a dominant-negative inhibitor of JNK are unable to form tumors, 3) JNK may play a novel role as a mediator of genotoxic stress by facilitating DNA repair. The DNA damaging agent cisplatin activates JNK. In T98G cells, blocking the JNK pathway inhibits DNA-repair, indicating that the JNK genotoxic stress response mediates DNA repair which may promote resistance to chemotherapy. A collaborative study with ISIS Pharmaceuticals was established to develop specific antisense JNK oligos, which have been shown to inhibit JNK. It is now proposed to 1) test the role of constitutive and EGF-dependent JNK activity human xenograft formation, 2) to use transient transfection assays to dissect the mechanism of JNK activation, 3) to determine whether JNK induces DNA repair enzyme synthesis, and 4) to carry out in vivo tests of the ability of the antisense oligonucleotides to inhibit xenografts and sensitize xenografts to chemo- and radio-therapy.
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