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Published online
doi:10.1083/jcb.200712078
The Journal of Cell Biology, Vol. 182, No. 1, 103-116
The Rockefeller University Press, 0021-9525 $30.00
© Szabo et al.
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Article

Calreticulin inhibits commitment to adipocyte differentiation



Eva Szabo1, Yuanyuan Qiu2, Shairaz Baksh3, Marek Michalak2, and Michal Opas1

1 Department of Laboratory Medicine and Pathobiology, Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada
2 Department of Biochemistry and 3 Department of Pediatrics and Child Health, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Correspondence to Michal Opas: m.opas{at}utoronto.ca

Calreticulin, an endoplasmic reticulum (ER) resident protein, affects many critical cellular functions, including protein folding and calcium homeostasis. Using embryonic stem cells and 3T3-L1 preadipocytes, we show that calreticulin modulates adipogenesis. We find that calreticulin-deficient cells show increased potency for adipogenesis when compared with wild-type or calreticulin-overexpressing cells. In the highly adipogenic crt–/– cells, the ER lumenal calcium concentration was reduced. Increasing the ER lumenal calcium concentration led to a decrease in adipogenesis. In calreticulin-deficient cells, the calmodulin–Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway was up-regulated, and inhibition of CaMKII reduced adipogenesis. Calreticulin inhibits adipogenesis via a negative feedback mechanism whereby the expression of calreticulin is initially up-regulated by peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}). This abundance of calreticulin subsequently negatively regulates the expression of PPAR{gamma}, lipoprotein lipase, CCAAT enhancer–binding protein {alpha}, and aP2. Thus, calreticulin appears to function as a Ca2+-dependent molecular switch that regulates commitment to adipocyte differentiation by preventing the expression and transcriptional activation of critical proadipogenic transcription factors.

E. Szabo and Y. Qiu contributed equally to this paper.

Abbreviations used in this paper: CaMKII, Ca2+/calmodulin-dependent protein kinase II; C/EBP, CCAAT enhancer–binding protein; ChIP, chromatin immunoprecipitation; CREB, cAMP response element binding; EB, embryoid body; EMSA, electrophoretic mobility shift assay; ES, embryonic stem; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; PPAR, peroxisome proliferator–activated receptor; PPRE, peroxisome proliferator responsive element; RA, retinoic acid; RXR, retinoid X receptor; WT, wild type.

© 2008 Szabo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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