Post‐transcriptional mechanisms regulating parathyroid hormone gene expression in secondary hyperparathyroidism. (9th April 2020)

• Record Type: Journal Article
• Authors: Kilav‐Levin, Rachel; Hassan, Alia; Nechama, Morris; Shilo, Vitali; Silver, Justin; Ben‐Dov, Iddo Z.; Naveh‐Many, Tally
• Is Part Of: FEBS journal. Volume 287:Number 14(2020)
• Page Start: 2903
• Page End: 2913
• Publication Date: 2020-04-09
• Subjects: AUF1 -- chronic kidney disease -- KSRP -- miRNA -- Pin1 -- protein -- Protein-mRNA binding -- mRNA interaction; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15300
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Parathyroid hormone (PTH) regulates serum calcium levels and bone strength. Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality. In experimental SHP, the increased PTH gene expression is due to increased PTH mRNA stability and is mediated by protein–PTH mRNA interactions. Adenosine–uridine‐rich binding factor 1 (AUF1) stabilizes and K‐homology splicing regulatory protein (KSRP) destabilizes PTH mRNA. The peptidyl‐prolyl cis/trans isomerase Pin1 acts on target proteins, including mRNA‐binding proteins. Pin1 leads to KSRP dephosphorylation, but in SHP, parathyroid Pin1 activity is decreased and phosphorylated KSRP fails to bind PTH mRNA, leading to increased PTH mRNA stability and levels. A further level of post‐transcriptional regulation occurs through microRNA (miRNA). Dicer mediates the final step of miRNA maturation. Parathyroid‐specific Dicer knockout mice that lack miRNAs in the parathyroid develop normally. Surprisingly, these mice fail to increase serum PTH in response to both hypocalcemia and CKD, indicating that parathyroid Dicer and miRNAs are essential for stimulation of the parathyroid. Human and rodent parathyroids share similar miRNA profiles that are altered in hyperparathyroidism. The evolutionary conservation of abundant miRNAs and their regulation in hyperparathyroidism indicate their significance in parathyroid physiology and pathophysiology. let‐7 and miR‐148 antagonism modifies PTH secretion in vivo and in vitro, suggesting roles for specific miRNAs in parathyroid function. This review summarizes the current knowledge on the post‐transcriptional mechanisms of PTH gene expression in SHP and the central contribution of miRNAs to the high serum PTH levels of both primary hyperparathyroidism and SHP. Abstract : Protein–mRNA interactions and miRNA determine the post‐transcriptional fate of many mRNAs. Parathyroid hormone (PTH) expression is increased in chronic kidney disease (CKD) patients correlating with morbidity and mortality. Decreased activity of the isomerase Pin1 modifies protein–PTH mRNA interactions to enhance PTH mRNA stability and levels in experimental chronic kidney failure. The stimulation of PTH expression is also dependent upon miRNAs that are dysregulated in CKD patients and experimental models.