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Mol Cell Biol, April 1998, p. 2334-2343, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Coupled Transcriptional and Translational Control of Cyclin-Dependent Kinase Inhibitor p18INK4c Expression during Myogenesis

Dawn E. Phelps,1 Kuang-Ming Hsiao,2,dagger Yan Li,1,Dagger Nanpin Hu,3 David S. Franklin,2 Eva Westphal,2 Eva Y.-H. P. Lee,2 and Yue Xiong1,2,4,*

Lineberger Comprehensive Cancer Center,1 Department of Biochemistry and Biophysics,2 and Program in Molecular Biology and Biotechnology,4 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3280, and Department of Molecular Medicine, Institute of Biotechnology and Center for Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-32073

Received 22 August 1997/Returned for modification 17 September 1997/Accepted 22 January 1998

Terminal differentiation of many cell types involves permanent withdrawal from the cell division cycle. The p18INK4c protein, a member of the p16/INK4 cyclin-dependent kinase (CDK) inhibitor family, is induced more than 50-fold during myogenic differentiation of mouse C2C12 myoblasts to become the predominant CDK inhibitor complexed with CDK4 and CDK6 in terminally differentiated myotubes. We have found that the p18INK4c gene expresses two mRNA transcripts---a 2.4-kb transcript, p18(L), and a 1.2-kb transcript, p18(S). In proliferating C2C12 myoblasts, only the larger p18(L) transcript is expressed from an upstream promoter. As C2C12 cells are induced to differentiate into permanently arrested myotubes, the abundance of the p18(L) transcript decreases. The smaller p18(S) transcript expressed from a downstream promoter becomes detectable by 12 h postinduction and is the predominant transcript expressed in terminally differentiated myotubes. Both transcripts contain coding exons 2 and 3, but p18(L) uniquely contains an additional noncoding 1.2-kb exon, exon 1, corresponding exclusively to the 5' untranslated region (5' UTR). The expression pattern of the shorter p18(S) transcript, but not that of the longer p18(L) transcript, correlates with terminal differentiation of muscle, lung, liver, thymus, and eye lens cells during mouse embryo development. The presence of the long 5' UTR in exon 1 attenuated the translation of p18(L) transcript, while its absence from the shorter p18(S) transcript resulted in significantly more efficient translation of the p18 protein. Our results demonstrate that during terminal muscle cell differentiation, induction of the p18 protein is regulated by promoter switching coupled with translational control.

* Corresponding author. Mailing address: 215 Fordham Hall, Campus Box 3280, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3280. Phone: (919) 962-2142. Fax: (919) 966-8799. E-mail: yxiong{at}email.unc.edu.

dagger Present address: Genetics Laboratory, Department of Life Science, Chung Shan Medical and Dental College, Taichung, Taiwan, Republic of China.

Dagger Present address: Clontech Laboratories, Inc., Palo Alto, CA 94303-4230.




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