REGULATION OF LIVER FUNCTION BY MAPK/MKP-1

Yale University, New Haven CT

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Abstract

The broad goal of this project is to understand the molecular mechanisms that control liver function in health[unreadable] and disease. Specifically, the aim of this project is to understand how local nuclear and cytosolic calcium[unreadable] signals integrate with the mitogen-activated protein kinase (MARK) signal transduction pathway in the[unreadable] control of liver growth, regeneration, and metabolism. The MAPKs are negatively regulated by a family of[unreadable] enzymes known as the MARK phosphatases (MKPs). Recent work from this laboratory has shown that the[unreadable] nuclear localized MKP family member, MKP-1, is essential for the negative regulation of the MAPKs. These[unreadable] observations are supported in vivo where we have discovered that mice lacking expression of MKP-1 exhibit[unreadable] enhanced MAPK activation in the liver which correlates with enhanced hepatic lipid metabolism and[unreadable] resistance to the acquisition of a fatty liver. We present preliminary data to support a new signaling[unreadable] paradigm in which cytosolic and nuclear calcium signals differentially regulate the transcription of MKP-1 in[unreadable] a positive and negative manner, respectively. This discrete regulation of MKP-1 in the nucleus by calcium[unreadable] controls MAPK-mediated gene expression. We hypothesize that local calcium signals regulates MKP-1[unreadable] expression which serves to limit the magnitude and spatio-temporal kinetics of MAPK-mediated gene[unreadable] activity required for liver growth, regeneration, and metabolic homeostasis. We will test this hypothesis in[unreadable] three specific aims. Aim 1 will define the molecular basis for the differential effects of nuclear and cytosolic[unreadable] calcium on the regulation of MKP-1 gene transcription by disrupting calcium signaling in these sub-cellular[unreadable] compartments using previously developed targeted calcium-binding proteins. Aim 2 will define the[unreadable] importance of MKP-1 nuclear localization for its physiological function in the liver. To test this, a novel[unreadable] genetic mutation in MKP-1 that targets it to the cytosol will be "knocked-in" to mice using an inducible[unreadable] CreLoxP approach. Aim 3 will determine the role of MKP-1 on liver growth, regeneration, and stress[unreadable] management using MKP 1 "knock-out" mice. Together with projects by Nathanson and Ehrlich, the proposed molecular,[unreadable] biochemical and genetic approaches in this project will establish a new signaling paradigm between local[unreadable] calcium signals, MKP-1 and MAPK-mediated gene expression in the control of liver function.[unreadable]