Abstract
A parathyroid hormone-related peptide (PTHRP) has been identified in human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The PTHRP and parathyroid hormone (PTH) genes appear to have arisen by duplication and to represent members of a gene family. PTHRP mRNAs have been demonstrated in a number of normal tissues, but little is known concerning the regulation of PTHRP gene expression in any site. We studied PTHRP gene expression in TT cells, a human C-cell line which also produces calcitonin and calcitonin gene-related peptide. We found that both the synthetic glucocorticoid, dexamethasone, and the active vitamin D metabolite, 1,25-dihydroxyvitamin D3, decreased steady-state PTHRP mRNA levels in TT cells in a time- and dose-dependent fashion. The dexamethasone effect was completely blocked by the glucocorticoid antagonist RU-486. 24,25-dihydroxyvitamin D3 was found to be inactive. Neither dexamethasone nor 1,25-dihydroxyvitamin D3 appeared to influence PTHRP mRNA stability in TT cells, and both agents were shown by nuclear transcription run-off assay to decrease PTHRP gene transcription. These findings indicate that the PTHRP gene is under the transcriptional control of glucocorticoids and vitamin D in a cell line with prototypical neuroendocrine features.
Highlights
A parathyroidhormone-relatedpeptide(PTHRP) has been identified in human tumors associated with thesyndromeofhumoralhypercalcemiaofmaligwhereas the parathyroid hormone (PTH) gene seems to be expressed exclusively in parathyroid cells [13], parathyroidhormone-related peptide (PTHRP) transcriptshave been identified in avariety of normal tissues, including sources as diverse nancy
We studied the regulation of PTHRP gene expression in TT cells, acontinuous human C-cell line derived from a medullary thyroid carcinoma [16].TT cells have neuroendocrine characteristics and produce both calcitonin and calcitonin gene-related peptide (CGRP) [16,17,18]
We have previously reported that poly(A)+ RNA prepared selected samples and analyzed by Northern analysis using a from TT cells contains the major 1.5- and 2.1-kb PTHRP coding region PTHRP RNA probe,confirming that equivalent mRNA species [15, 19] that have been identified in RNAs reductions in the1.5- and 2.1-kb PTHRP mRNA species were from a variety of human tumors and normal tissues and/or observed in response tobothdexamethasoneand cells[5,15, 20]
Summary
(OH),D3 influenced y-actin mRNA, analyzed as an internal control (Figs. 1 and 2). Poly(A)+RNA was prepared from. Glucocorticoid antagonist RU-486 [30] completely blocketdhe Both steroids have beperneviously shown to influence steady-response to 100nM dexamethasone, whereas 1p~ RU-486 by state calcitonin mRNA in TT cells [17, 18], and these re- itself has no influence on the level of PTHRP mRNA (data sponses were used inthepresentexperimentsas positive not shown)A. t 100 nM, 24,25-OH2D3had noeffect on PTHRP controls. Calcitonin mRNA is abundant inTT cells and was mRNA (not shown). We first examined the timceourse of the effectsof 100 nM and 1,25-(OH)2D3-induceddecreases in steady-state PTHRP dexamethasone (Fig. 1)and 100 nM 1,25-(OH)2D3(Fig. 2) on mRNA levels. PTHRP and calcitonin mRNA levels in TT cells. C ao ence the PTHRP mRNA disappearance rat(eFig. 4)
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