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| Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules |
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| Author(s): Gum R, Juarez J, Allgayer H, Mazar A, Wang Y, Boyd D |
| Source: ONCOGENE Volume: 17 Issue: 2 Pages: 213-225 Published: JUL 16 1998 |
| Times Cited: 40 References: 109 |
| Abstract: The urokinase-type plasminogen activator receptor (u-PAR) has been implicated in tumor progression, and previous studies have shown that the expression of this gene is strongly up-regulated by PMA, Although the signaling mechanism by which PMA modulates u-PAR expression is not known, the effect of this phorbol ester on the expression of other genes has been ascribed to activation of the c-Raf-1-ERK signaling pathway. However, in the current study we examined an alternate possibility that the inductive effect of PMA on u-PAR expression also required a JNK1-dependent signaling cascade usually associated with stress-inducing stimuli. PMA treatment of the u-PAR-deficient OVCAR-3 ovarian cancer cells, which contain low JNK activities, resulted in a rapid (5 min) increase in JNK activity, Maximal JNK activity (12-fold induction) occurred after 30 min; this preceding the earliest detected rise in u-PAR protein (2 h), Dose-response studies with PMA also indicated that the increased JNK activity was tightly correlated with elevated u-PAR protein levels. The stimulation of u-PAR promoter activity by PMA required an intact upstream AP-1 motif (- 184) and in PMA-treated cells this motif was bound with c-Jun as indicated from mobility shift assays, PMA up-regulated the c-Jun trans acting activity as indicated by the higher activity of a GAL4-regulated luciferase reporter in phorbol-ester-treated cells co-transfected with an expression vector encoding the c-Jun transactivation domain fused to the GAL4 DNA-binding domain, The ability of PMA to stimulate u-PAR promoter activity was effectively titrated out by the co-expression of either a kinase-defective JNK1 or a dominant negative MEKK1 the latter being an upstream activator of JNK1, Conversely, u-PAR promoter activity was stimulated by the co-expression of a constitutively active MEKK1 and this induction was antagonized by the inclusion of the kinase-defective JNK1 plasmid, We also determined the biological significance of the JNK1-dependent signaling cascade in regulating u-PAR promoter activity by c-Ha-ras since this oncogene is activated and/or overexpressed in a variety of tumors including ovarian cancer. Transfection of an activated c-Ha-ras into OVCAR-3 cells stimulated u-PAR promoter activity over 20-fold and this could be countered by the individual expression of dominant negative expression constructs to Rac-1, MEKK1 or JNK1, Taken together, these data suggest that the PMA- or c-Ha-Ras-dependent stimulation of u-PAR gene expression requires a JNK1-dependent signaling module and that, at least for PMA, the concurrent stimulation of a JNK1-independent signaling module is also required. Thus, caution should be exercised in invoking linear signaling modules to account for the regulation of inducible gene expression. |
| Document Type: Review |
| Language: English |
| Reprint Address: Boyd, D (reprint author), Univ Texas, MD Anderson Cancer Ctr, Dept Tumor Biol, 1515 Holcombe Blvd,Box 108, Houston, TX 77030 USA |
Addresses:
1. Univ Texas, MD Anderson Cancer Ctr, Dept Tumor Biol Head & Neck Surg, Houston, TX 77030 USA
2. Angstrom Pharmaceut, San Diego, CA USA
3. Univ Sydney, Westmead Hosp, Dept Renal Med, Westmead, NSW 2145 Australia
4. SmithKline Beecham, Dept Mol Immunol, King Of Prussia, PA 19406 USA |
| Publisher: STOCKTON PRESS, HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND |
| Subject Category: Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity |
| IDS Number: ZZ211 |
| ISSN: 0950-9232 |
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