Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation

p27 is a key regulator of cell proliferation through inhibition of G, cyclin-dependent kinase (CE)K) 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 eukargotic 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.