Cell Death Promoting Mechanisms of Mst1

Univ Of Med/Dent Of Nj-Nj Medical School, Newark NJ

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Abstract

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