Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia

Shilo, Vitali; Ben‐Dov, Iddo Z.; Nechama, Morris; Silver, Justin; Naveh-Many, Tally

doi:10.1096/fj.15-274191

Cited by 38 publications

(44 citation statements)

References 46 publications

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“…PTH secretion, gene expression, cell proliferation and the increased PTH secretion after acute hypocalcaemia were all dependent on Dicer1. In addition, the development of sHPT of both chronic hypocalcaemia and uraemia in these mice was dependent on parathyroid miRNAs .…”

Section: Micrornasmentioning

confidence: 95%

“…Expression of a subset of miRNAs might discriminate between PA and PC, but this needs to be validated in larger tumour cohorts. The role of miRNAs in normal parathyroid function was recently investigated using parathyroid‐specific DICER1‐knockout mice . DICER1 deletion blocked the processing of pre‐miRNAs and thereby prevented mature miRNA expression in general.…”

Section: Micrornasmentioning

confidence: 99%

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Molecular genetics and epigenetics of nonfamilial (sporadic) parathyroid tumours

Westin

2016

J Intern Med

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Primary hyperparathyroidism (pHPT) is a common endocrine disease characterized by excessive secretion of parathyroid hormone and an increased level of serum calcium. Overall, 80–85% of pHPT cases are due to a benign, single parathyroid adenoma (PA), and 15% to multiglandular disease (multiple adenomas/hyperplasia). Parathyroid carcinoma (PC) is rare, accounting for <0.5–1% of pHPT cases. Secondary hyperparathyroidism (sHPT) is a complication of renal failure, with the development of parathyroid tumours and hypercalcaemia. Recurrent mutations in the MEN1 gene have been confirmed by the whole‐exome sequencing in 35% of PAs, suggesting that non‐protein‐coding genes, regulatory elements or epigenetic derangements may also have roles in the majority of PAs. DNA translocations with cyclin D1 overexpression occur in PAs (8%). In PCs, mutations in CDC73/HRPT2 are common. Activation of the WNT/β‐catenin signalling pathway (accumulation of nonphosphorylated β‐catenin) by an aberrantly truncated LRP5 receptor has been seen for the majority of investigated PAs and sHPT tumours, and possibly by APC inactivation through promoter methylation in PCs. Promoter methylation of several other genes and repressive histone H3 lysine 27 trimethylation by EZH2 of the HIC1 gene may also contribute to parathyroid tumorigenesis. It is possible that a common pathway exists for parathyroid tumour development. CCND1 (cyclin D1) and EZH2 overexpression, accumulation of nonphosphorylated β‐catenin and repression of HIC1 have all been observed to occur in PAs, PCs and sHPT tumours. In addition, hypermethylation has been observed for the same genes in PAs and PCs (e.g. SFRP1, CDKN2A and WT1). Whether β‐catenin represents a ‘hub’ in parathyroid tumour development will be discussed.

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Section: Micrornasmentioning

confidence: 95%

Section: Micrornasmentioning

confidence: 99%

Molecular genetics and epigenetics of nonfamilial (sporadic) parathyroid tumours

Westin

2016

J Intern Med

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“…The PT-Dicer À/À mice also had an impaired increase in serum PTH, PTH mRNA, and parathyroid cell proliferation after both chronic hypocalcemia and uremia. 8 Therefore, miRNAs are essential for the stimulation of the parathyroid by hypocalcemia and uremia. miRNA profiling by deep sequencing in parathyroid glands from experimental hyperparathyroidism models and patients receiving dialysis showed that human and rodent parathyroids share similar miRNA profiles.…”

Section: See Basic Research On Page 54mentioning

confidence: 99%

Transcription factors that determine parathyroid development power PTH expression

Naveh-Many

Silver

2018

Kidney International

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“…Altered expression of miRNAs may well have an important role in development of parathyroid tumors and miRNAs have been implicated in parathyroid function. Dicer-dependent maturation of parathyroid miRNAs is responsible for the dysregulated control of PTH secretion in a uremic mouse model of secondary hyperparathyroidism (Shilo et al, 2015 ). However, specific miRNAs that directly affect parathyroid CaSR expression have yet to be identified.…”

Section: The Casr Genementioning

confidence: 99%

Calcium-Sensing Receptor Gene: Regulation of Expression

Hendy

Canaff

2016

Front. Physiol.

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The human calcium-sensing receptor gene (CASR) has 8 exons, and localizes to chromosome 3q. Exons 1A and 1B encode alternative 5′-untranslated regions (UTRs) that splice to exon 2 encoding the AUG initiation codon. Exons 2–7 encode the CaSR protein of 1078 amino acids. Promoter P1 has TATA and CCAAT boxes upstream of exon 1A, and promoter P2 has Sp1/3 motifs at the start site of exon 1B. Exon 1A transcripts from the P1 promoter are reduced in parathyroid tumors and colon carcinomas. Studies of colon carcinomas and neuroblastomas have emphasized the importance of epigenetic changes—promoter methylation of the GC-rich P2 promoter, histone acetylation—as well as involvement of microRNAs in bringing about CASR gene silencing and reduced CaSR expression. Functional cis-elements in the CASR promoters responsive to 1,25-dihydroxyvitamin D [1,25(OH)2D], proinflammatory cytokines, and the transcription factor glial cells missing-2 (GCM2) have been characterized. Reduced levels of CaSR and reduced responsiveness to active vitamin D in parathyroid neoplasia and colon carcinoma may blunt the “tumor suppressor” activity of the CaSR. The hypocalcemia of critically ill patients with burn injury or sepsis is associated with CASR gene upregulation by TNF-alpha and IL-1beta via kappaB elements, and by IL-6 via Stat1/3 and Sp1/3 elements in the CASR gene promoters, respectively. The CASR is transactivated by GCM2—the expression of which is essential for parathyroid gland development. Hyperactive forms of GCM2 may contribute to later parathyroid hyperactivity or tumorigenesis. The expression of the CaSR—the calciostat—is regulated physiologically and pathophysiologically at the gene level.

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Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia

Cited by 38 publications

References 46 publications

Molecular genetics and epigenetics of nonfamilial (sporadic) parathyroid tumours

Molecular genetics and epigenetics of nonfamilial (sporadic) parathyroid tumours

Transcription factors that determine parathyroid development power PTH expression

Calcium-Sensing Receptor Gene: Regulation of Expression

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