Tissue-specific regulation of serum response factor

Serum Response Factor (SRF) is a member of the MADS (MCM1, Agamous and Deficiens, SRF) box family of transcription factors and is an important regulator of many genes associated with cell growth and differentiation. SRF is a 67kDa phosphoprotein that binds as a dimer to CC(A/T)₆GG, referred to as a serum response element (SRE). SRF and its homologs regulate the expression of genes involved in determining cell fate in plants, yeast, Drosophila , mouse, and humans. The diverse patterns of regulated genes by SRF homologs have required these transcription factors to develop complex mechanisms to regulate transcriptional activity within specific cell-types.; SRF is necessary for the transcription of many muscle-specific genes during the differentiation of pluripotential progenitor cells into terminally differentiated muscle cells. SRF also regulates many of the cardiac genes dysregulated during the progression of cardiac hypertrophy as characterized by the induction of the “fetal gene expression program,” which consists of c-fos, β-myosin heavy chain, and ANF. The endogenous expression pattern of the SRF gene is restricted to the myocardium and differentiating smooth and skeletal muscle cells during early embryogenesis. To begin to understand the molecular mechanisms and signaling pathways involved in embryogenesis and cellular differentiation of myogenic lineages, it is important to characterize the cis-acting elements that regulate tissue-restricted and context-dependent expression of SRF.; Previous work from our lab has identified the minimal regulatory sequences and critical cis-acting elements in the SRF promoter that are necessary for proper regulation of the SRF gene in serum stimulated fibroblast cells. However, little is known about the mechanisms responsible for regulating tissue-specific expression of SRF in myocytes. Therefore, I focused my studies on two areas: (1) Regulation of SRF gene expression in cardiomyocytes during hypertrophy, and (2) Regulation of SRF gene expression in the developing mouse embryo.; The fast question was premised on previous observations that (1) myocardial tissue from rodents with age induced cardiac hypertrophy had elevated SRF protein levels relative to non-hypertrophic animals, and (2) transgenic mice that cardiac-specifically overexpressed SRF prematurely died of severe cardiac hypertrophy. (Abstract shortened by UMI.)...