EUKARYOTIC TRANSLATION INITIATION-FACTOR 4E REGULATES EXPRESSION OF CYCLIN D1 AT TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL LEVELS

Regulation of the cell cycle is orchestrated by cyclins and cyclin-dep endent kinases. We have demonstrated previously that overexpression of eukaryotic translation initiation factor 4E (eIF-4E) in NIH 3T3 cells growing in 10% fetal calf serum leads to highly elevated levels of cy clin D1 protein without significant increase in cyclin D1 mRNA levels, suggesting that a post-transcriptional mechanism is involved. (Rosenw ald, I. B., Lazaris-Karatzas, A., Sonenberg, N., and Schmidt, E. V. (1 993) Mol. Cell. Biol. 13, 7358-7363). In the present reseach, we did n ot find any significant effect of eIF-4E on polysomal distribution of cyclin D1 mRNA. However, the total amount of cyclin D1 mRNA associated with polysomes was significantly increased by eIF-4E overexpression. Further, we determined that the levels of both cyclin D1 protein and m RNA are increased in serum-deprived cells overexpressing eIF-4E. Nucle ar run-on experiments demonstrated that the rate of the cyclin D1 tran scription is not down-regulated in serum-deprived cells overexpressing eIF-4E. Thus, elevated levels of eIF-4E may lead to increased transcr iption of the cyclin D1 gene, and this effect becomes visible when ser um deprivation down-regulates the rate of cyclin D1 mRNA synthesis in control cells. However, artificial overexpression of cyclin D1 mRNA in serum-deprived cells in the absence of eIF-4E overexpression did not cause the elevation of cyclin D1 protein, and this overexpressed cycli n D1 mRNA accumulated in the nucleus, suggesting that one post-transcr iptional role of eIF-4E is to transport cyclin D1 mRNA from the nucleu s to cytoplasmic polysomes.