Eukaryotic Translation Initiation Factor 4E Regulates Expression of Cyclin D1 at Transcriptional and Post-transcriptional Levels

doi:10.1074/jbc.270.36.21176

Eukaryotic Translation Initiation Factor 4E Regulates Expression of Cyclin D1 at Transcriptional and Post-transcriptional Levels (*)

From the (1)Harvard-Massachusetts Institutes of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, the
(2)Harvard Medical School Hematology-Oncology Division, Brigham & Women's Hospital, Boston, Massachusetts 02115, the
(3)Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada, and the
(4)Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129

^§ Supported by a grant from Johnson & Johnson. To whom correspondence should be addressed:
Dept. of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635.
Tel.: 908-235-5526; Fax: 908-235-4073.

↵^¶ Present address: Dept. of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602.

Abstract

Regulation of the cell cycle is orchestrated by cyclins and cyclin-dependent 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 cyclin D1 protein without significant increase in cyclin D1 mRNA levels, suggesting that a post-transcriptional mechanism is involved. (Rosenwald, I. B., Lazaris-Karatzas, A., Sonenberg, N., and Schmidt, E. V.(1993) Mol. Cell. Biol. 13, 7358-7363). In the present reseach, we did not 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 mRNA are increased in serum-deprived cells overexpressing eIF-4E. Nuclear run-on experiments demonstrated that the rate of the cyclin D1 transcription is not down-regulated in serum-deprived cells overexpressing eIF-4E. Thus, elevated levels of eIF-4E may lead to increased transcription of the cyclin D1 gene, and this effect becomes visible when serum 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 cyclin D1 mRNA accumulated in the nucleus, suggesting that one post-transcriptional role of eIF-4E is to transport cyclin D1 mRNA from the nucleus to cytoplasmic polysomes.

Footnotes

↵* This work was supported in part by a research grant from Johnson & Johnson (to P. L. and I. M. L.), National Institutes of Health Grants DK-16272 (to J.-J. C.) and GM-42504 (to L. G.), United States Public Health Service Grant R01-CA63117-01 (to E. V. S.), and a grant from the Medical Research Council and National Cancer Institutes of Canada (to N. S.). The first two authors contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

eIF-4E

eukaryotic translation initiation factor 4E

MMTV

mouse mammary tumor virus

FCS

fetal calf serum.
↵²D. Rousseau, R. Kaspar, I. B. Rosenwald, L. Gehrke, and N. Sonenberg, manuscript in preparation.
↵³D. Rousseau, R. Kaspar, I. B. Rosenwald, L. Gehrke, and N. Sonenberg, manuscript in preparation.
- Received April 14, 1995.