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Cyclin B and E2F-1 Expression in Prostate Carcinoma Cells Treated with the Novel Retinoid CD437 Are Regulated by the Ubiquitin-mediated Pathway¹

John D. Dingell VA Medical Center and Karmanos Cancer Institute, and Department Internal Medicine, Wayne State University, Detroit, Michigan 48201 [L. F., A. K. R., Y. Z., C. T., E. V. B., J. A. F.]; Burnham Institute, La Jolla, California 92037 [M. D.]; Galderma R&D, Sophia Antipolis, France [U. R.]; and the Department Cell Biology, Harvard Medical School, Boston, Massachusetts 02015 [G. F., M. W. K.]

E2F-1 and cyclin B are important regulators of the cell cycle, and their expressionand degradation are tightly regulated. Proteolysis of both molecules is mediated by the ubiquitin degradation pathway involving the activation of specific E3 ubiquitin ligases. Treatment of prostate carcinoma cells with the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437/AHPN) results in the enhanced expression of E2F-1 and rapid degradation of cyclin B in the absence of the modulation of mRNA levels; this is accompanied by the S phase arrest of the cells and subsequent apoptosis. The elevated level of E2F-1 is because of the enhanced stability of the molecule, as indicated by pulse-labeling studies, demonstrating a prolonged half-life. The enhanced E2F-1 stability is associated with the concomitant acetylation of E2F-1, the disassociation of E2F-1 from the E2F-1 E3 ligase p45^SKP2, and decreased E2F-1 ubiquitination, suggesting CD437 inhibition of E-3 E2F-1 ligase activity. Exposure of the cells to CD437 also results in the enhanced association of the cyclin B E3 ligase APC with cyclin B and the rapid proteolysis of cyclin B. The CD437-enhanced proteolysis of cyclin B is blocked in the presence of the ubiquitin proteolysis inhibitor N-acetyl-leu-leu-norleu-al. Thus, CD437 modulates the expression of E2F-1 and cyclin B through the simultaneous stimulation and inhibition of the cyclin B and E2F-1 E3 ligases, respectively.

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