We have shown previously that a positive feedback (amplification) mechanism between the stressresponsive protein kinases, including mammalian sterile 20 like kinase 1 (Mst1), and the cell deathpromoting mechanisms is critical in mediating cardiac myocyte apoptosis. In particular, activation of Mst1plays a critical role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion (I/R). Mst1also plays an important role in mediating cardiac dysfunction during cardiac remodeling after myocardialinfarction (Ml). Detailed analyses regarding the cellular function of Mst1 have suggested that the proapoptoickinase Mst1 not only mediates cardiac myocyte apoptosis but also initiates multiple other cellulareffects, such as inhibition of compensatory hypertrophy and downregulation of mitochondrial geneexpression, intimately contributing to the development of cardiac dysfunction. Our analyses regarding thedownstream targets of Mst1 have suggested that 1) an evolutionary conserved signaling pathway consistingof hWW45 and Lats2 mediates the proapoptotic effects of Mst1; 2) Mst1 phosphorylates PERK, anendoplasmic reticulum (ER) kinase, thereby initiating ER stress responses; 3) Mstl downregulatesexpression of mitochondrial genes through downregulation and transcriptional inactivation of PGC-1 alpha.Our goals are to further demonstrate the importance of these Mst1 targets in mediating heart failure inresponse to I/R and during cardiac remodeling. We hypothesize that: A. hWW45-Lats2 mediates the proapoptoticfunction of Mst1. B. Mst1 activates PERK, thereby mimicking ER stress in the heart. C. Mst1phosphorylates PGC-1 alpha, thereby inhibiting expression of nuclear encoded mitochondrial genes. We willaddress these issues using newly developed transgenic mouse models as well as in vitro studies designedto determine the underlying molecular mechanisms. Our study will establish the novel linkage between thepro-apoptotic signaling mechanism and the downstream mechanisms leading to cardiac dysfunction.Knowledge obtained from this study should be useful for the development of novel modalities for treatment ofischemic heart diseases and congestive heart failure.
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