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This version published online on October 28, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0108
A more recent version of this article appeared on February 1, 2005
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Submitted on March 16, 2004
Accepted on October 20, 2004

The protein phosphatase calcineurin determines basal parathyroid hormone gene expression

Osnat Bell, Elena Gaberman, Rachel Kilav, Ronen Levi, Keith B. Cox, Jeffery D. Molkentin, Justin Silver, and Tally Naveh-Many*

Minerva Center for Calcium and Bone Metabolism, Nephrology Services, The Hadassah Hebrew University Medical Center, Jerusalem, Israel; Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Cincinnati, Ohio, USA

* To whom correspondence should be addressed. E-mail: tally{at}cc.huji.ac.il.

Calcium and phosphate regulate PTH mRNA stability through differences in binding of parathyroid proteins to a minimal 63nt cis acting instability element in its 3'-UTR. One of these proteins is AUF1 whose levels are not regulated in parathyroid extracts from rats fed the different diets. However, two-dimensional gels showed post-translational modification of AUF1 that included phosphorylation. There is no parathyroid (PT) cell line but in HEK293 cells the 63 nt element is recognized as an instability element and RNAi for AUF1 decreased human PTH secretion in co-transfection experiments. Stably transfected cells with a chimeric GH gene containing the PTH 63nt cis acting element were used to study the signal transduction pathway that regulates AUF1 modification and chimeric gene mRNA stability. Cyclosporine A, the calcineurin inhibitor, regulated AUF1 post-translationally and this correlated with an increase in the stability of GH-PTH 63nt mRNA but not of the control GH mRNA. Mice with genetic deletion of the calcineurin A{beta} gene had markedly increased PTH mRNA levels that were still regulated by low calcium and phosphorus diets. Therefore, calcineurin regulates AUF1 post-translationally in vitro and PTH gene expression in vivo, but still allows its physiological regulation by calcium and phosphate.




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