CREB/ATF PROTEINS, GROWTH AND DIFFERENTIATION

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Signal transduction pathways converge ultimately at the level of transcriptional activation to produce specific patterns of gene expression in response to environmental stimuli. The initiation of transcription mediated by these signalling pathways is regulated by the coordinate expression and/or activation of specific transcription factors that bind to the control regions of genes. Specific insights into the mechanisms underlying transcriptional activation have recently arisen from studies of the structure and functions of these transcription factors. The CREB/ATF family of transcriptional transactivating proteins has only recently been discovered and appears to provide a link between the regulation of gene expression in response to activators of cellular signalling pathways and the regulation of gene expression by viral transactivating proteins. In the present application we propose to identify the role(s) of CREB and ATF-2 in the processes of growth and differentiation by utilizing constitutively active and dominant negative versions of these proteins to influence the growth of FRTL-5 cells and the differentiation of L6E9 cells. The use of this strategy obviates the need to investigate the role of each member of this large family of proteins that mediate transcriptional events by the common mechanism of sequence-specific binding to the CRE regulatory motif. The model systems to be studied were chosen because they exhibit defined phenotypic changes in response to the elevation of intracellular levels of cAMP. Understanding the nature and importance of the role(s) of these proteins in the mechanisms of growth and differentiation in normal cells will have profound influences on the understanding of these processes during oncogenesis.