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The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism
Morris Nechama, … , Justin Silver, Tally Naveh-Many
Morris Nechama, … , Justin Silver, Tally Naveh-Many
Published September 21, 2009
Citation Information: J Clin Invest. 2009;119(10):3102-3114. https://doi.org/10.1172/JCI39522.
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Research Article

The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism

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Abstract

Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3′ UTR region. As the peptidyl-prolyl isomerase (PPIase) Pin1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of Pin1 in regulating PTH mRNA stability in rat parathyroids and transfected cells. The data generated were consistent with Pin1 being a PTH mRNA destabilizing protein. Initial analysis indicated that Pin1 activity was decreased in parathyroid protein extracts from both hypocalcemic and CKD rats and that pharmacologic inhibition of Pin1 increased PTH mRNA levels posttranscriptionally in rat parathyroid and in transfected cells. Pin1 mediated its effects via interaction with KSRP, which led to KSRP dephosphorylation and activation. In the rat parathyroid, Pin1 inhibition decreased KSRP–PTH mRNA interactions, increasing PTH mRNA levels. Furthermore, Pin1–/– mice displayed increased serum PTH and PTH mRNA levels, suggesting that Pin1 determines basal PTH expression in vivo. These results demonstrate that Pin1 is a key mediator of PTH mRNA stability and indicate a role for Pin1 in the pathogenesis of secondary hyperparathyroidism in individuals with CKD.

Authors

Morris Nechama, Takafumi Uchida, Irit Mor Yosef-Levi, Justin Silver, Tally Naveh-Many

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Figure 2

Pin1 inhibition by juglone increases PTH mRNA in vivo posttranscriptionally.

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Pin1 inhibition by juglone increases PTH mRNA in vivo posttranscriptiona...
(A and B) Juglone i.p. (A) PPIase activity assays of parathyroid cytoplasmic lysates from rats injected i.p. with juglone or vehicle. (B) Serum PTH in rats as in A. (C–F) Juglone applied topically. (C) PPIase activity of parathyroid cytoplasmic lysates from rats treated with juglone or vehicle applied topically; data in A and C are presented as mean ± SEM (n = 3) from 1 of 3 repeat experiments; P < 0.05 at 5–30 seconds. (D) Immunoblots of the extracts in C for Pin1 and GAPDH. (E) Northern blots of PTH mRNA levels after juglone, in rats as in C. The lanes were run on the same gel but were noncontiguous (white line). (F) qRT-PCR analysis for PTH mRNA in rat parathyroids as in C; *P < 0.05. (G) Nuclear run-ons of PTH transcription in isolated nuclei of parathyroids from 5 rats in each group after topical juglone (J) or vehicle (C). (H) Quantification of PTH mRNA transcription in G, showing no difference in PTH transcription. The same result was obtained in a repeat experiment. (I) RNase protection analysis (RPA) of total parathyroid RNA from rats after topical juglone or vehicle. Left panels: RPA using an antisense probe for the PTH mRNA 3′ UTR or for control GAPDH mRNA. Right panel: RPA using an antisense probe for the first intron (newly transcribed pre–PTH mRNA). The intact probes before and after RNase treatment (arrows to the left and right of the gels, respectively) and hybridization with tRNA as a nonspecific control are shown. Juglone increased PTH mRNA but not the pre–PTH mRNA or GAPDH mRNA.

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