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Mol. Cell. Biol. 21 (15): 4960-4967

Copyright © 2001 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, August 2001, p. 4960-4967, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.4960-4967.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Control of Cyclin-Dependent Kinase Inhibitor p27 Expression by Cap-Independent Translation

W. Keith Miskimins,* Gang Wang, Michelle Hawkinson, and Robin Miskimins

Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, South Dakota 57069

Received 14 August 2000/Returned for modification 27 September 2000/Accepted 3 May 2001

p27 is a key regulator of cell proliferation through inhibition of G1 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.

* Corresponding author. Mailing address: University of South Dakota School of Medicine, Division of Basic Biomedical Sciences, 414 E. Clark St., Vermillion, SD 57069. Phone: (605) 677-5132. Fax: (605) 677-6381. E-mail: kmiskimi{at}

Molecular and Cellular Biology, August 2001, p. 4960-4967, Vol. 21, No. 15
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.15.4960-4967.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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