Chapter 11.5 - Proteomic Analysis of MEF2 Post-Translational Regulation in the Heart

Abstract

This chapter discusses the control of cardiac specific gene expression by myocyte enhancer factor 2 (MEF2) transcriptional regulatory proteins and loss-of-function analysis in gene-targeted mice that has positioned these factors at a key nexus in muscle control circuitry. The MEF2 family of transcription factors are initially expressed in the early mesodermal progenitor populations that give rise to the cardiac crescent at 7.5 days post-coitum (dpc) in the mouse. The MEF2s belong to the MADS superfamily of DNA-binding proteins. The amino terminus of MEF2 proteins is conserved among all family members, and consists of a 57–amino acid MADS domain and a 29–amino acid MEF2 domain that together mediate MEF2 protein dimerization, cofactor interaction, and binding to a cognate cis element with the consensus (T/C)TA(A/T)4TA(G/A). The MEF2 transactivation domain (TAD) is located in the carboxy terminus, and the sequence in this region is more divergent between MEF2 family members. MEF2s have already been shown to be highly responsive to several signal transduction cascades, and their post-translational regulation by covalent modification by PKC, p38 MAPK, ERK5, CDK5, and CK2 has been well-documented. In addition, a further level of control of the MEF2s involves protein–protein interactions. MEF2 has previously been shown to physically interact with MyoD, Class II HDACs, GATA4, p300, Sp1, Smad2, myocardin, and MASTR. Thus, combinations of post-translational modifications and interactions with regulatory protein partners create a unique integrated code for the regulation of MEF2 function, underlying the diverse roles that MEF2 presides over in development and postnatal physiology.