We have shown previously that a positive feedback (amplification) mechanism between the stress? responsive protein kinases, including mammalian sterile 20 like kinase 1 (Mst1), and the cell death? promoting mechanisms is critical in mediating cardiac myocyte apoptosis. In particular, activation of Mst1? plays a critical role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion (I/R). Mst1? also plays an important role in mediating cardiac dysfunction during cardiac remodeling after myocardial? infarction (Ml). Detailed analyses regarding the cellular function of Mst1 have suggested that the proapoptoic? kinase Mst1 not only mediates cardiac myocyte apoptosis but also initiates multiple other cellular? effects, such as inhibition of compensatory hypertrophy and downregulation of mitochondrial gene? expression, intimately contributing to the development of cardiac dysfunction. Our analyses regarding the? downstream targets of Mst1 have suggested that 1) an evolutionary conserved signaling pathway consisting? of hWW45 and Lats2 mediates the proapoptotic effects of Mst1; 2) Mst1 phosphorylates PERK, an? endoplasmic reticulum (ER) kinase, thereby initiating ER stress responses; 3) Mstl downregulates? expression 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 in? response to I/R and during cardiac remodeling. We hypothesize that: A. hWW45-Lats2 mediates the proapoptotic? function of Mst1. B. Mst1 activates PERK, thereby mimicking ER stress in the heart. C. Mst1? phosphorylates PGC-1 alpha, thereby inhibiting expression of nuclear encoded mitochondrial genes. We will? address these issues using newly developed transgenic mouse models as well as in vitro studies designed? to determine the underlying molecular mechanisms. Our study will establish the novel linkage between the? pro-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 of? ischemic heart diseases and congestive heart failure.
Showing the most recent 10 out of 196 publications
