This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bell, O. Articles by Naveh-Many, T. Search for Related Content PubMed PubMed Citation Articles by Bell, O. Articles by Naveh-Many, T.

The Protein Phosphatase Calcineurin Determines Basal Parathyroid Hormone Gene Expression

Minerva Center for Calcium and Bone Metabolism (O.B., E.G., R.K., R.L., J.S., T.N.-M.), Nephrology Services, The Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; and Department of Pediatrics (K.B.C., J.D.M.), University of Cincinnati, Children’s Hospital Medical Center, Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Tally Naveh-Many, Ph.D., Nephrology Services, Hadassah Hospital, P.O. Box 12000, Jerusalem 91120, Israel. E-mail: tally{at}cc.huji.ac.il.

Calcium and phosphate regulate PTH mRNA stability through differences in binding of parathyroid (PT) proteins to a minimal 63-nucleotide (nt) cis-acting instability element in its 3'-untranslated region. One of these proteins is adenosine-uridine-rich binding factor (AUF1), whose levels are not regulated in PT extracts from rats fed the different diets. However, two-dimensional gels showed posttranslational modification of AUF1 that included phosphorylation. There is no PT cell line, but in HEK 293 cells the 63-nt element is recognized as an instability element, and RNA interference for AUF1 decreased human PTH secretion in cotransfection experiments. Stably transfected cells with a chimeric GH gene containing the PTH 63-nt 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 posttranslationally, and this correlated with an increase in the stability of GH-PTH 63-nt mRNA but not of the control GH mRNA. Mice with genetic deletion of the calcineurin Aß gene had markedly increased PTH mRNA levels that were still regulated by low calcium and phosphorus diets. Therefore, calcineurin regulates AUF1 posttranslationally in vitro and PTH gene expression in vivo but still allows its physiological regulation by calcium and phosphate.

This article has been cited by other articles:

				M. Nechama, I. Z. Ben-Dov, P. Briata, R. Gherzi, and T. Naveh-Many The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels FASEB J, October 1, 2008; 22(10): 3458 - 3468. [Abstract] [Full Text] [PDF]

				J. V. Chakkalakal, P. Miura, G. Belanger, R. N. Michel, and B. J. Jasmin Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU-rich element and calcineurin signaling Nucleic Acids Res., February 11, 2008; 36(3): 826 - 838. [Abstract] [Full Text] [PDF]

				N. H. Ing, D. A. Massuto, and L. A. Jaeger Estradiol Up-regulates AUF1p45 Binding to Stabilizing Regions within the 3'-Untranslated Region of Estrogen Receptor {alpha} mRNA J. Biol. Chem., January 18, 2008; 283(3): 1764 - 1772. [Abstract] [Full Text] [PDF]

				C. S Ritter, S. Pande, I. Krits, E. Slatopolsky, and A. J Brown Destabilization of parathyroid hormone mRNA by extracellular Ca2+ and the calcimimetic R-568 in parathyroid cells: role of cytosolic Ca and requirement for gene transcription J. Mol. Endocrinol., January 1, 2008; 40(1): 13 - 21. [Abstract] [Full Text] [PDF]

				M. Dinur, R. Kilav, A. Sela-Brown, H. Jacquemin-Sablon, and T. Naveh-Many In Vitro Evidence that Upstream of N-ras Participates in the Regulation of Parathyroid Hormone Messenger Ribonucleic Acid Stability Mol. Endocrinol., July 1, 2006; 20(7): 1652 - 1660. [Abstract] [Full Text] [PDF]

				J V Warner, D R Nyholt, F Busfield, M Epstein, J Burgess, S Stranks, P Hill, D Perry-Keene, D Learoyd, B Robinson, et al. Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3-14. J. Med. Genet., March 1, 2006; 43(3): e12 - e12. [Abstract] [Full Text] [PDF]

				R. Levi, I. Z. Ben-Dov, V. Lavi-Moshayoff, M. Dinur, D. Martin, T. Naveh-Many, and J. Silver Increased Parathyroid Hormone Gene Expression in Secondary Hyperparathyroidism of Experimental Uremia Is Reversed by Calcimimetics: Correlation with Posttranslational Modification of the Trans Acting Factor AUF1 J. Am. Soc. Nephrol., January 1, 2006; 17(1): 107 - 112. [Abstract] [Full Text] [PDF]

				T. Kawata, Y. Imanishi, K. Kobayashi, N. Onoda, Y. Takemoto, H. Tahara, S. Okuno, E. Ishimura, T. Miki, T. Ishikawa, et al. Direct in Vitro Evidence of Extracellular Ca2+-Induced Amino-Terminal Truncation of Human Parathyroid Hormone (1-84) by Human Parathyroid Cells J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5774 - 5778. [Abstract] [Full Text] [PDF]