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Translational Regulation of Cyclin D1 by 15-Deoxy-^12,14-Prostaglandin J₂¹

Biomedical Sciences Division and Biology Department, University of California, Riverside, California 92521-0121 [P. A. C., C-H. H., T. B., D. S. S.], and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106 [S. D., C. E. S.]

The D-group cyclins play a key role in the progression of cells through the G₁ phase of the cell cycle. Treatment of MCF-7 breast cancer cells with the cyclopentenone prostaglandin 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂) results in rapid down-regulation of cyclin D1 protein expression and growth arrest in the G₀/G₁ phase of the cell cycle. 15d-PGJ₂ also down-regulates the expression of cyclin D1 mRNA; however, this effect is delayed relative to the effect on cyclin D1 protein levels, suggesting that the regulation of cyclin D1 occurs at least partly at the level of translation or protein turnover. Treatment of MCF-7 cells with 15d-PGJ₂ leads to a rapid increase in the phosphorylation of protein synthesis initiation factor eukaryotic initiation factor 2 (eIF-2) and a shift of cyclin D1 mRNA from the polysome-associated to free mRNA fraction, indicating that 15d-PGJ₂ inhibits the initiation of cyclin D1 mRNA translation. The selective rapid decrease in cyclin D1 protein accumulation is facilitated by its rapid turnover (t_1/2=34 min) after inhibition of cyclin D1 protein synthesis. The half-life of cyclin D1 protein is not significantly altered in cells treated with 15d-PGJ₂. Treatment of cells with 15d-PGJ₂ results in strong induction of heat shock protein 70 (HSP70) gene expression, suggesting that 15d-PGJ₂ might activate protein kinase R (PKR), an eIF-2 kinase shown previously to be responsive to agents that induce stress. 15d-PGJ₂ strongly stimulates eIF-2 phosphorylation and down-regulates cyclin D1 expression in a cell line derived from wild-type mouse embryo fibroblasts but has an attenuated effect in PKR-null cells, providing evidence that PKR is involved in mediating the effect of 15d-PGJ₂ on eIF-2 phosphorylation and cyclin D1 expression. In summary, treatment of MCF-7 cells with 15d-PGJ₂ results in increased phosphorylation of eIF-2 and inhibition of cyclin D1 mRNA translation initiation. At later time points, repression of cyclin D1 mRNA expression may also contribute to the decrease in cyclin D1 protein.

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