Vascular smooth muscle cells respond to a diverse array of extracellular ligands acting through cell surface receptors, many of which have been implicated as causative factors in vascular disease. Although these initiate complex streams of intracellular signaling information, little is known about how this complexity is integrated. Receptor signaling is well known to control transcriptionally acting processes, whereas little is known about control of processes that act at the post-transcriptional level. We propose to focus on mechanisms of the latter in the context of the problem of signaling integration. Our general hypothesis is that regulated post-transcriptional mechanisms in smooth muscle cells play as important a role in controlling immediate early gene expression as do regulated transcriptional mechanisms. We plan to develop three specific themes: i) To understand in one system whether multiple signaling pathways modulate functional post-transcriptional mechanisms. ii) To demonstrate that simultaneously triggered transcriptional and post-transcriptional mechanisms can cooperate synergistically in specifying immediate-early mRNA responses evoked by a stimulus. iii) To make progress in identifying molecular factors and/or molecular mechanisms that function as trans-acting agents mediating post-transcriptional responsiveness to receptor signaling. Our four specific aims are to: 1) To test the hypothesis that the 5' untranslated region of the vascular AT1 -R mRNA interacts with a complex of factors that include substrates of cAMP-dependent kinase signaling. 2) To test the hypothesis that mitogen-induced immediate-early COX 2 gene expression involves coordinate activation of factors that simultaneously function at transcriptional and post-transcriptional levels. 3) To test the hypothesis that signaling pathways and mechanisms involved in controlling immediate-early post-transcriptional modulation of IL-6 gene expression differ from those involved in COX 2 gene induction. 4) To test the hypothesis that changes in gene expression by activation of the 0 protein-coupled mating pheromone pathway in yeast can involve post-transcriptional mechanisms. This course of research will clarify both how the VSMC phenotype integrates signal transduction information and will continue solid progress in understanding the molecular and cellular basis of post-transcriptional regulation in gene expression.
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