ROLE OF CAMP IN GROWTH CONTROL AND DIFFERENTIATION--GENE REGULATION

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In prokaryotes, cAMP is known to regulate the transcription of specific genes by a well-defined mechanism. cAMP binds to the prokaryotic cAMP binding protein CRP (cAMP receptor protein)/CAP (catabolite gene activator protein), and this complex interacts with specific DNA sequences at the 5 ends of targeted genes, modulating the ability of RNA polymerase to bind to the promoters. In mammalian cells, gene expression is altered in response to stimulation by hormones. Stimuli whose action is mediated through adenylate cyclase and cAMP-dependent protein kinase influence the transcriptional efficiency of several genes through the binding of specific factors to distinct cis-acting DNA sequences, CRE (cAMP responsive element), located in the 5 noncoding (promoter) region. Recently, a region containing the CRE has been shown to bind specific nuclear proteins from various tissues. Recent evidence suggests that transcriptional regulation of eukaryotic genes by cAMP requires a cAMP-dependent protein kinase. In this study, we examined the role of cAMP-dependent protein kinase in gene transcription. Since cAMP-dependent protein kinase is exclusively present in the cytoplasm, any nuclear function of the protein kinase must be accompanied by its translocation to the nucleus. It was found that the ras gene suppression, growth inhibition, differentiation (leukemic cells), and phenotypic reversion of Ha-MuSV-transformed NIH/3T3 cells by site-selective cAMP analogs correlated with the nuclear translocation of the RII cAMP receptor protein, the regulatory subunit of protein kinase type II, which was detected within 10 min after the analog treatment. Thus, the nuclear translocation of the RII cAMP receptor protein is an early event in the cAMP regulation of growth and differentiation. The goal of this study is to provide direct evidence of interaction between the cAMP consensus sequences and cAMP receptor protein (RII) and/or a phosphoprotein substrate of protein kinase.