For the effects on cell cycle progression or gene expression associated with individual cyclin types to be manifested, specific phosphorylation of selected substrates must occur. However, the mechanism of substrate selection and phosphoryiation by cyclin- dependent kinase complexes is not well understood. The E proteins (such as the products of the E2A gene) form homodimers and heterodimers with other bHLH proteins that are important in reguiating tissue-speccic gene expression. We have shown that activtion of transcription by certain E protein heterodimers is inhibited by cyclin D-1 dependent kinases. We have evidence that inhibition of myogenic BHLH regulators by cyclin dD1-dependent kinases is mediated by E protein dependent kase sites. Studies are proposed to investigate the mechanism of inhibition, and to determine how cyclin D1-dependent lltase complexes specifically recognize E protein heterodimers and homodimers as substrates. Independent of their function as transcriptional actors, expression of the E2A gene products can induce growth arrest in certin cell lines. We will investigate further how the E2A gene products act as growth suppressors, and will determine whether interactions with cyclin D1-dependent kinases play a critical role in this function. The spliceform products of the E2A also play a critical role in normal Bell development. Mantle cell lymphoma is associated with a chromosomal translocation that activates expression of the cyclin D1 gene. We will begin to investigate the hypothesis that enhanced expression of cyclin D1 contributes to the development of mantle cell lymphoma by blocking the functions of E2A gene products in growth control of mantle B- cells.
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