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TC Groves, GF Wagner, and GE DiMattia

Stanniocalcin (STC) is a glycoprotein hormone first discovered in fish as a homeostatic regulator of calcium and phosphate transport; it has recently been discovered in mammals, in which it appears to have a similar role. It has also been implicated in a number of different physiological processes through correlative studies, but the factors regulating its production have not been elucidated. In this report, we show that steady-state STC mRNA levels in the mouse corticotrope tumor line, AtT-20, were exquisitely sensitive to glucocorticoids. Hydrocortisone and dexamethasone (Dex) induced a dramatic reduction in steady-state STC mRNA levels in AtT-20 cells through a post-transcriptional mechanism. Similarly, glucocorticoids down-regulated STC mRNA levels in the human fibrosarcoma cell line, HT1080. The specificity of the glucocorticoid-mediated decrease in STC mRNA abundance was shown using the glucocorticoid receptor antagonist, RU-486. Activation of the cAMP-signaling pathway in glucocorticoid-cultured AtT-20 cells transiently restored STC gene expression. Treatment of AtT-20 cells with the transcriptional inhibitor, actinomycin D, rescued steady-state STC mRNA levels from Dex-induced repression, indicating that the Dex-mediated decrease in STC gene expression requires current gene transcription. Taken together, these results describe a unique model system in which cAMP-stimulated events can reverse post-transcriptional repression of gene expression by glucocorticoids.

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CR McCudden, MR Kogon, GE DiMattia, and GF Wagner

It is currently accepted that the fish stanniocalcin (STC) gene is expressed exclusively in the corpuscles of Stannius (CS), unique endocrine glands on the kidneys of bony fishes. In this study, we have re-examined the pattern of fish STC gene expression in the light of the recent evidence for widespread expression of the gene in mammals. Surprisingly, we found by Northern blotting that the fish gene was also expressed in the kidneys and gonads, in addition to the CS glands. Moreover, Southern blotting of RT-PCR products revealed STC mRNA transcripts in all tissues assayed, including brain, heart, gill, muscle and intestine. In situ hybridization studies using digoxigenin-labeled riboprobes localized STC mRNA to chondrocytes, and both mature and developing nephritic tubules. Immunocytochemical staining indicated that the STC protein was widespread in cells of the gill, kidney, brain, eye, pseudobranch and skin. We also characterized the salmon STC gene, establishing that it was comprised of five exons as opposed to four in mammals. A single transcription start site was identified by primer extension 99 bp upstream of the start codon. This is the first evidence of STC gene expression in fish tissues other than the CS glands and suggests that, as in mammals, fish STC operates via both local and endocrine pathways.

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CK Wong, HY Yeung, NK Mak, GE DiMattia, DK Chan, and GF Wagner

Stanniocalcin is a polypeptide hormone that was first reported in fish as a regulator of mineral metabolism. Its recent identification in mammals has opened a new area of investigation in basic and clinical endocrinology. In the present study, regulation of the stanniocalcin (STC) and stanniocalcin related protein (STCrP) genes were investigated in mouse neuroblastoma cells (Neuro-2A) in relation to neuronal cell differentiation. Neuro-2A is an undifferentiated cell line that contains measurable levels of STCrP mRNA, but undetectable levels of STC mRNA. Treatment of the cells with either dbcAMP (1-4 mM) or 50 microM euxanthone (PW1) resulted in extensive differentiation and neurite outgrowth. However, only neurites of dbcAMP-treated cells developed varicosities, a phenotypic marker of axon formation. Furthermore, following differentiation induced by dbcAMP, there was an upregulation of STC and downregulation of STCrP mRNA levels. In the first 24 and 48 h of treatments, there was a maximum twofold induction and 1.5-fold reduction in STC and STCrP mRNAs respectively. Following 96 h of treatment, an additional 14-fold STC induction and 1.2-fold STCrP reduction were observed. The increase in STC mRNA levels was accompanied by a concomitant increase in axon-specific low molecular form microtubule-associated protein (MAP-2c) mRNA and varicosities on the neurites, suggesting a possible role for STC in axonogenesis. There was no induction of STC mRNA levels when PW1 was added into the culture media, whereas ionomycin (1-10 microM) had no observable effects on cell differentiation or STC/STCrP mRNA. Immunocytochemical staining of dbcAMP-treated cells revealed abundant levels of immunoreactive STC, particularly in the varicosities, with only weak staining in control, untreated cells. Antisense oligodeoxynucleotides transfection studies indicated that the expression of STC was a cause of varicosity formation and a consequence of cell differentiation. Our findings lend further support to the notion that STC is involved in the process of neural differentiation.