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M Wong, M S Ramayya, G P Chrousos, P H Driggers, and K L Parker


The orphan nuclear receptor steroidogenic factor 1 (SF-1) plays key roles in endocrine development and function. Initially identified as a positive regulator of the cytochrome P450 steroid hydroxylases, analyses of knockout mice deficient in SF-1 revealed that SF-1 is essential for adrenal and gonadal development, pituitary gonadotropin expression and formation of the ventromedial hypothalamic nucleus. Although more limited in scope, analyses of SF-1 in humans similarly have suggested that SF-1 is important for differentiated function in adrenocortical and gonadotrope adenomas. In the hope of extending our understanding of SF-1 function by identifying possible roles of SF-1 in clinical endocrine disorders, we isolated the FTZ-F1 gene encoding human SF-1 and mapped it to chromosome 9q33. In this report, we characterize the sequence and structural organization of the human cDNA and gene encoding SF-1, providing new insights into comparative aspects of SF-1 structure that will facilitate efforts to study the role of this transcription factor in human endocrine disorders.

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H Namihira, M Sato, K Murao, WM Cao, S Matsubara, H Imachi, M Niimi, H Dobashi, NC Wong, and T Ishida

Menin is a protein encoded by the gene mutated in multiple endocrine neoplasia type 1 (MEN1) characterized by multiple endocrine tumors of the parathyroid glands, pancreatic islets and the anterior pituitary, especially prolactinoma. In this study, we examined the effects of menin on human prolactin (hPRL) expression. In rat pituitary GH3 cells stably expressing menin, both PRL gene expression/secretion and thymidine incorporation into DNA were inhibited as compared with mock-transfected cells. The transcriptional activity of PRL promoter in GH3 cells co-transfected with menin was significantly decreased. A deletion mutation (569 delC), which we identified in a Japanese MEN1 family, was introduced into menin. When GH3 cells were transfected with a mutant menin expression vector, inhibition of hPRL promoter activity was partially reversed. These observations suggest that menin inhibits hPRL promoter activity and cell proliferation, raising the possibility that menin might play an important role in the tumorigenesis of prolactinoma.

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R S Guenette, H B Corbeil, J Léger, K Wong, V Mézl, M Mooibroek, and M Tenniswood


After weaning, the mammary gland ceases lactation and involutes. The wet weight of the gland decreases by 70% within 4 days of weaning. This involves significant tissue remodelling as the ducts regress and return to the resting state. The presence of apoptotic bodies in the luminal epithelial compartment 2 to 3 days after weaning provides clear evidence that a substantial proportion of the regression is attributable to the induction of active cell death (ACD) of the epithelial cells.

These changes in the architecture of the gland were found to be mirrored by changes in gene expression. The steady-state level of β-casein mRNA decreased rapidly after weaning from the high levels seen during lactation to undetectable levels by 8 days after weaning. The steady-state levels of expression of a number of genes associated with ACD, including TRPM-2, tissue transglutaminase (TGase) and poly(ADP-ribose) polymerase (PARP), increased transiently during this time-frame. The steady-state level of TRPM-2 mRNA increased 2 days after weaning, reaching a peak on day 4, and decreasing to undetectable levels by day 8 after weaning. The steady-state levels of two other mRNAs, TGase and PARP, showed very similar kinetics. In contrast, the mRNA for Hsp 27, which has been shown to be induced during prostate regression, was not significantly induced in the regressing mammary gland. In-situ hybridization demonstrated that the TRPM-2, TGase and PARP genes were expressed predominantly in the luminal epithelial cells of the ducts. These cells expressed β-casein mRNA during lactation, and underwent ACD after weaning.

While the ultrastructural changes in the mammary gland after weaning, and the induction of TRPM-2, TGase and PARP mRNAs, are reminiscent of apoptosis in the prostate, several features of the process are different. Most notably, the disruption of the secretory processes and the lack of increased expression of Hsp 27 in the regressing mammary gland suggest that there may be a number of important events in ACD that are not common to all cells.

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Kent Wehmeier, Luisa M Onstead-Haas, Norman C W Wong, Arshag D Mooradian, and Michael J Haas

The vitamin D metabolite 24,25-dihydroxyvitamin D3 (24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25-[OH]2D3 but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3 has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3 modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3 to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3 resulted in decreased peroxisome proliferator-activated receptor alpha (PPARα) expression and retinoid-X-receptor alpha (RXRα) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3 for 1–3 h induced PKCα activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-jun phosphorylation, an increase in AP-1-dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3 increased IL-1β, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3 elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function.