Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels.
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 research, 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.
Rosenwald
I B
IB
Harvard-Massachusetts Institutes of Technology Division of Health Sciences and Technology, Cambridge 02139, USA.
Kaspar
R
R
Rousseau
D
D
Gehrke
L
L
Leboulch
P
P
Chen
J J
JJ
Schmidt
E V
EV
Sonenberg
N
N
London
I M
IM
D016475:3T3 Cells; D000818:Animals; D001769:Blood; D002455:Cell Division / Q000235:genetics; D016895:Culture Media, Serum-Free; D019938:Cyclin D1; D016213:Cyclins / Q000235:genetics*; D039561:Eukaryotic Initiation Factor-4E; D005786:Gene Expression Regulation; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D016895:Culture Media, Serum-Free; D016213:Cyclins; D039561:Eukaryotic Initiation Factor-4E; D015513:Oncogene Proteins; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D019938:Cyclin D1