Two critical aspects of cell differentiation are permanent withdrawal from active cell division cycle and preventing terminally differentiated cells from re-entering the cell cycle. Molecular pathways that regulate cell differentiation must inevitably interact with those that regulate the cell cycle. Primary control of the eukaryotic cell cycle requires functional cyclin-dependent kinases, or CDKs. CDK activity can be negatively regulated by a number of inhibitory proteins. These CDK inhibitors may play a key role in regulating cell cycle withdrawal during and/or maintaining permanent cell cycle arrest after cell differentiation. Correlative data-suggests a potential function for one CDK inhibitor, p18, in causing and maintaining cell cycle arrest during myogenesis. This proposal is aimed at directly testing this hypothesis. To determine the direct role for p18 in myogenesis, p18 function has been successfully negated using antisense technology. Utilizing antisense technology to lower p18 levels at different phases of myogenesis, I will examine whether p18 is required for initiation of myogenesis, formation of myotubes, and the maintenance of cell cycle arrest in terminally differentiated myotubes. The regulation of p18 gene expression during myogenesis will also be analyzed. To accomplish this, the genomic and mRNA structure of p18 will be determined. Finally, transcriptional regulation of p18 expression will be examined by assessing whether the two p18 transcripts are regulated from two distinct promoters during myogenesis.
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