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- Title
Calreticulin signal upstream of calcineurin and MEF2C in a critical Ca<sup>2+</sup>-dependent signaling cascade.
- Authors
Lynch, Jeffrey; Guo, Lel; Gelebart, Pascal; Chilibeck, Kaari; Jian Xu; Molkentin, Jeffery D.; Agellon, Luis B.; Michalak, Marek
- Abstract
We uncovered a new pathway of interplay between calreticulin and myocyteenhoncer factor (MEF) 2C, a cardiac-specific transcription factor. We establish that calreticulin works up- stream of calcineurin and MEF2C in a Ca2-dependent signal transduction cascade that links the endoplasmic reticulum and the nucleus during cardiac development. In the absence of calreticulin, translocation of MEF2C to the nucleus is compromised. This defect is reversed by calreticulin itself or by a constitutively active form of calcineurin. Furthermore, we show that expression of the calreticulin gene itself is regulated by MEF2C in vitro and in vivo and that, in turn, increased expression of caireticulin affects MEF2C transcriptional activity. The present findings provide a clear molecular explanation for the embryonic lethality observed in calreticulin-deficient mice and emphasize the importance of caireticulin in the early stages of cardiac development. Our study illustrates the existence of a positive feedback mechanism that ensures an adequate supply of releasable Ca is maintained within the cell for activation of calcineurin and, subsequently, for proper functioning of MEF2C.
- Publication
Journal of Cell Biology, 2005, Vol 170, Issue 1, p37
- ISSN
0021-9525
- Publication type
Academic Journal
- DOI
10.1083/jcb.200412156