Abstract
The negative calcium responsive elements of the parathyroid hormone gene bind to a specific set of nuclear proteins in an extracellular calcium (Ca2+e)-dependent manner. We have found that one of the negative calcium responsive elements, named oligo B, is found in the 5'-flanking region of such vasoactive genes as the vasopressin and atrial natriuretic polypeptide genes. Furthermore, the oligo B-like sequence in the former gene is conserved throughout evolution. Because expression of some of these vasoactive genes is altered by external stimuli which change cell volume, we examined whether oligo B is involved in gene regulation by hyperosmolarity. Here, we demonstrate that the binding between oligo B and its binding nuclear proteins including a redox factor 1 was reduced by hyperosmolarity generated by sodium chloride but not by urea. Such attenuated binding was reversed by dephosphorylating nuclear proteins by a potato acid phosphatase, suggesting that NaCl treatment elicited phosphorylation of these nuclear proteins to weaken their binding activity to oligo B. Furthermore, these nuclear events led to hyperosmolarity-mediated transcriptional stimulation of the genes bearing this DNA element in the cultured cells.
Highlights
To maintain a constant cell volume against extracellular osmotic perturbations, virtually all living cells must be equipped with sensing machineries that transmit information from the cell membrane to the nucleus
We previously reported that a DNA sequence similar to oligo B was found in the upstream region of the rat atrial natriuretic polypeptide (ANP) and vasopressin genes [11]
Vasopressin, whose transcription is known to be stimulated by hyperosmolarity [14], contains DNA sequences similar to oligo B, and these sequences are conserved throughout evolution (Fig. 1)
Summary
To maintain a constant cell volume against extracellular osmotic perturbations, virtually all living cells must be equipped with sensing machineries that transmit information from the cell membrane to the nucleus. Cells of the mammalian renal medulla are exposed to markedly elevated concentrations of NaCl and urea as a consequence of the renal concentrating mechanism In these cells, a large but physiological elevation of the osmolarity activates certain ion channels and the mitogen-activated protein kinase cascade followed by up-regulation of some of the immediate early gene, resulting in an interaction between a transcription factor(s) and a specific DNA element(s) in cell nucleus (6 –9). In the upstream region of the human parathyroid hormone gene, two DNA elements interact with ubiquitous nuclear proteins including Ref in a sequence-specific manner to mediate negative gene regulation by Ca2ϩe (10 –13). We examined the possibility that oligo B mediates osmolarity-induced regulation of gene expression in the cell nucleus
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