Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation.
p27 is a key regulator of cell proliferation through inhibition of G(1) cyclin-dependent kinase (CDK) activity. Translation of the p27 mRNA is an important control mechanism for determining cellular levels of the inhibitor. Nearly all eukaryotic mRNAs are translated through a mechanism involving recognition of the 5' cap by eukaryotic initiation factor 4E (eIF4E). In quiescent cells eIF4E activity is repressed, leading to a global decline in translation rates. In contrast, p27 translation is highest during quiescence, suggesting that it escapes the general repression of translational initiation. We show that the 5' untranslated region (5'-UTR) of the p27 mRNA mediates cap-independent translation. This activity is unaffected by conditions in which eIF4E is inhibited. In D6P2T cells, elevated cyclic AMP levels cause a rapid withdrawal from the cell cycle that is correlated with a striking increase in p27. Under these same conditions, cap-independent translation from the p27 5'-UTR is enhanced. These results indicate that regulation of internal initiation of translation is an important determinant of p27 protein levels.
Miskimins
W K
WK
Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, South Dakota 57069, USA. kmiskimi@usd.edu
Wang
G
G
Hawkinson
M
M
Miskimins
R
R
D016475:3T3 Cells; D020121:5' Untranslated Regions; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018076:DNA, Complementary / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D010448:Peptide Initiation Factors / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
D020121:5' Untranslated Regions; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D039561:Eukaryotic Initiation Factor-4E; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000242:Cyclic AMP; D008156:Luciferases