| Calreticulin is a Ca2+-binding protein essential for heart development. At present, there is an incomplete understanding of: (1) genes of the fetal cardiac program; (2) transcription factors involved in activation of these genes; and, (3) Ca2+-dependent signaling pathways involved in activation of these transcription factors. It is believed that a better understanding of Ca2+-dependent signaling pathways will permit identification of novel drug targets to prevent, treat, and perhaps even cure many forms of cardiomyopathy. In this study, I investigated what cardiac transcription factors regulate cardiac expression of the calreticulin gene and identified myocyte enhancer factor 2C (MEF2C) as a strong activator. Examination of MEF2C cellular localization in calreticulin-deficient cells enabled identification of a novel signaling pathway in cardiomyocytes linking Ca2+ released by calreticulin to calcineurin activation and dephosphorylation of MEF2C. Calcineurin dephosphorylation of MEF2C carboxyl-terminus was necessary for MEF2C to translocate to the nucleus to impact target genes. The finding that MEF2C activates the calreticulin gene suggests the existence of a novel positive feedback mechanism in cells. In this feedback, MEF2C targets the gene of a Ca2+-binding protein thereby ensuring an adequate supply of releasable Ca2+ be maintained within the cell for calcineurin activation and MEF2C nuclear translocation. Results of this investigation emphasize the importance of calreticulin in early stages of cardiac development and suggest a possible molecular explanation for embryonic lethality observed in calreticulin-deficient mice as well as insight as to how expression of activated-calcineurin in the heart rescues calreticulin-deficient phenotype. |
