Abstract
Histological analyses showed that expression of the parathyroid calcium-sensing receptor (CaSR) is decreased in parathyroid adenomas. Because reduced expression of CaSR may result in insufficient suppression of parathyroid hormone secretion, the elucidation of regulatory mechanisms of CaSR expression is indispensable for understanding the pathogenesis of parathyroid adenomas. Two cDNA clones for human CaSR with different 5'-untranslated regions have been isolated. However, the structure of the promoter region of human CaSR and the mechanisms of production of multiple CaSR mRNAs are unknown. We have cloned promoter regions of human CaSR by screening a genomic library. The human CaSR gene has two promoters and two 5'-untranslated exons (exons 1A and 1B), and alternative usage of these exons leads to production of multiple CaSR mRNAs. The upstream promoter has TATA and CAAT boxes, and the downstream promoter is GC-rich. Northern blot analysis showed that expression levels of exon 1A in parathyroid adenomas are significantly less than those in normal glands. However, expression of exon 1B was not different between adenomas and normal glands. Thus, specific reduction of the transcript driven by the upstream promoter was observed in parathyroid adenomas. Further analyses of factors that modulate the activity of the upstream promoter are necessary to clarify the pathogenesis of parathyroid adenomas.
Highlights
The parathyroid calcium-sensing receptor (CaSR)1 plays pivotal roles in the regulation of parathyroid hormone (PTH) secretion and serum calcium levels
Because reduced expression of CaSR may result in insufficient suppression of PTH secretion, the elucidation of the regulatory mechanisms of CaSR expression is indispensable for understanding the pathogenesis of parathyroid adenomas
The results indicate that the human CaSR gene has at least two promoters and that alternative usage of 5Ј-untranslated exons leads to the production of multiple CaSR mRNAs
Summary
CaSR, calcium-sensing receptor; PTH, parathyroid hormone; PCR, polymerase chain reaction; kb, kilobase(s); 5Ј-RACE, 5Ј-rapid amplification of cDNA ends; bp, base pair(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase. No mutation in the CaSR gene has been reported in parathyroid adenomas from patients with primary hyperparathyroidism, the most common cause of hypercalcemia [8]. It has been shown by immunohistochemistry and in situ hybridization that the expression of CaSR is decreased in parathyroid adenomas (9 –11). The results indicate that the human CaSR gene has at least two promoters and that alternative usage of 5Ј-untranslated exons leads to the production of multiple CaSR mRNAs. In addition, the expression of CaSR mRNA produced by one of the two promoters of the CaSR gene is reduced in parathyroid adenomas
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