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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA063783-05
Application #
2467962
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1993-09-22
Project End
2002-07-31
Budget Start
1997-09-30
Budget End
1998-07-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sidney Kimmel Cancer Center
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92121
Hayakawa, Jun; Mittal, Shalu; Wang, Yipeng et al. (2004) Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress. Mol Cell 16:521-35
Hayakawa, Jun; Depatie, Chantal; Ohmichi, Masahide et al. (2003) The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. J Biol Chem 278:20582-92
Yang, Yong-Min; Bost, Frederic; Charbono, Wilfried et al. (2003) C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma. Clin Cancer Res 9:391-401
Cripe, L D; Gelfanov, V M; Smith, E A et al. (2002) Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation. Leukemia 16:799-812
Gjerset, R; Haghighi, A; Lebedeva, S et al. (2001) Gene therapy approaches to sensitization of human prostate carcinoma to cisplatin by adenoviral expression of p53 and by antisense jun kinase oligonucleotide methods. Methods Mol Biol 175:495-520
Potapova, O; Gorospe, M; Bost, F et al. (2000) c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells. J Biol Chem 275:24767-75
de Belle, I; Mercola, D; Adamson, E D (2000) Method for cloning in vivo targets of the Egr-1 transcription factor. Biotechniques 29:162-9
Liu, C; Yao, J; Mercola, D et al. (2000) The transcription factor EGR-1 directly transactivates the fibronectin gene and enhances attachment of human glioblastoma cell line U251. J Biol Chem 275:20315-23
Hayakawa, J; Ohmichi, M; Kurachi, H et al. (1999) Inhibition of extracellular signal-regulated protein kinase or c-Jun N-terminal protein kinase cascade, differentially activated by cisplatin, sensitizes human ovarian cancer cell line. J Biol Chem 274:31648-54
Liu, C; Yao, J; de Belle, I et al. (1999) The transcription factor EGR-1 suppresses transformation of human fibrosarcoma HT1080 cells by coordinated induction of transforming growth factor-beta1, fibronectin, and plasminogen activator inhibitor-1. J Biol Chem 274:4400-11

Showing the most recent 10 out of 22 publications