The overexpression of the cylD1/PRAD1 gene has been implicated in several cancers. The role that cylD1/PRAD1 plays in tumorigenesis has not been elucidated and the normal transcriptional regulation of the cylD1/PRAD1 gene is not yet determined. The synthesis of cylD1 and E occurs in G1, these G1 specific cyclins are thought to regulate events during the G1 phase of the cell cycle that lead to proliferation. We have found that growth factors act synergistically to up-regulate the expression of cylD1 mRNA during G1. This regulation is, in part, through transcriptional control of the cylD1 gene. We have found that the increase in cylD1 transcription is independent of protein synthesis while the shut-off of this increased transcription is dependent on protein synthesis. Alterations in the transcriptional regulation of cylD1 could lead to its overexpression and uncontrolled cell growth. We have proposed experiments to determine how growth factors regulate the transcription of the cylD1 gene. This information will allow us to determine how normal cylD1 gene expression can be altered. For example, our preliminary data show that activated ras protein induces cylD1 expression through a protein kinase C-dependent pathway. We have also proposed experiments to determine where in the G1 phase cyclin D1 and cyclin E function. We will also determine which growth factor pathways are altered by overexpression of the G1 specific cyclins. Finally, since our data show that expression of cylD1 alone does not allow growth, we will determine what other growth factor/cell cycle specific protein or processes are required for traverse of the cell cycle. Our proposed studies will be performed in a well-defined growth factor regulated cell system. The data we obtain will enable us to determine if overexpression of cylD1 and/or cyclin E alter one or more normal cell cycle regulatory event. We will use this information to determine how cyclins participate in neoplastic transformation.
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