This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The broad, long term objectives of this research are to understand the biochemical relationships between G protein-coupled receptor (GPCR) signaling as they relate to the control of apoptosis. Programmed cell death is a tightly regulated biological process that is important not only for the normal progression of tissue development but also is a significant part of the immune response that results in the elimination of damaged or harmful cells. Aberration of this tightly regulated process contributes to the pathophysiological conditions found in cancer and neurodegenerative diseases. Although, there has been considerable information describing the specific signaling pathways of apoptosis, there is little understanding of how this essential biological response is effectively regulated. Heat shock proteins (HSPs) represent an emerging model for the coordinated, multistep regulation of apoptotic signaling events. This interactive network of proteins functions to renature misfolded proteins in response to damaging stimuli and thus has the ability to suppress the effects of apoptosis. Certain specifics of the biochemistry associated with HSP antiapoptotic effects are known. However, little information is found describing the regulation of HSPs in response to harmful stimuli. Activation of beta-adrenergic receptor (BAR) signaling mechanisms has been shown to modulate apoptotic phenotypes in cardiovascular models of apoptosis. Evidence suggests that a potential mechanism for this BAR modulation of apoptosis is mediated through a beta-arrestin signaling complex. However, the molecular components of the beta-arrestin complex that modulates apoptosis are not well understood. Using in vitro and in situ techniques, we recently established that association of a small heat shock protein (HSP27) with beta-arrestin in human urothelial (UROtsa) cells following pre-incubation with the selective BAR agonist, isoproterenol (ISO), was sufficient and necessary to protect against programmed cell death by subsequent challenge with an inducer of apoptosis. Our hypothesis is that formation of the BAR 'signalosome' is a mechanism by which the modulatory effects on programmed cell death are mediated through a specific beta-arrestin homologue, which in association with HSP27 is cytoprotective through a tyrosine kinase dependent pathway in the cell. The following studies are focused in order to establish the accuracy of our stated premise: 1) Reduced UROtsa cell expression of beta-arrestin homologue one or two reverses the BAR regulation of an apoptotic stimulus through a specific BAR subtype. 2) Agonist-dependent modulation of programmed cell death requires recruitment of mitogen activated protein kinases (MAPK) to the BAR.
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