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Y Myal, B Iwasiow, H Cosby, A Yarmill, A Blanchard, D Tsuyuki, A Fresnoza, ML Duckworth and RP Shiu

The human prolactin-inducible protein/gross cystic disease fluid protein-15 (PIP/GCDFP-15) gene is expressed in more than 90% of human breast cancer biopsies but not in the normal mammary gland. However, it is expressed in several normal human apocrine glands such as the lacrimal and salivary glands. In human breast cancer cell lines, the gene is regulated by a number of hormones including androgen and prolactin. It is not known whether gene expression in normal tissues is under similar hormonal control. To understand the mechanisms by which hormone- and tissue-specific expression of the human PIP/GCDFP-15 gene are regulated in vivo, we generated transgenic mice using a 13.7 kb genomic DNA fragment containing the entire 7 kb human gene, together with 2.9 kilobases of 5' and 3.8 kilobases of 3' flanking sequences. The human PIP/GCDFP-15 transgene was found to be expressed in both the lacrimal and salivary glands but was not expressed in the mammary glands of transgenic mice. This tissue-specific pattern of the transgene expression in the mouse was very similar to that of the endogenous human PIP/GCDFP-15 gene, and to the endogenous mouse,gene. In the mouse salivary glands, the transgene expression was highest in the parotid, considerably less in the submaxillary (submandibular) and absent in the sublingual glands. In the mouse lacrimal gland, as in the human breast cancer cell lines, the human PIP/GCDFP-15 transgene was also up-regulated by androgen. These studies demonstrate that the human gene with its 6.3 kb flanking sequences is able to confer gene expression in vivo in a tissue-specific and hormone-responsive manner.

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I Chakraborty, S K Das, J Wang and S K Dey

ABSTRACT

Cyclo-oxygenase (COX) is a rate-limiting enzyme that converts arachidonic acid to prostaglandins (PGs) and exists in two isoforms, COX-1 and COX-2. In the rodent, increased uterine vascular permeability at sites of blastocyst apposition is one of the earliest prerequisite events in the implantation process. This event is preceded by generalized uterine edema and luminal closure, and coincides with the initial attachment reaction between the trophectoderm and luminal epithelium. Vasoactive PGs are implicated in these processes. Here we demonstrate that COX genes are differentially regulated in the peri-implantation mouse uterus. During the preimplantation period (days 1–4), the COX-1 gene was expressed in the uterine epithelium mainly on day 4 until the initiation of attachment reaction in the evening after which the expression was downregulated. This COX-1 expression coincides with the generalized uterine edema required for luminal closure. In contrast, the COX-2 gene was expressed in the luminal epithelium and subepithelial stromal cells at the anti-mesometrial pole exclusively surrounding the blastocyst at the time of attachment reaction on day 4 and persisted through the morning of day 5. This uterine gene was not expressed at the sites of blastocyst apposition during progesterone (P4) treated delayed implantation, but was readily induced in the uterus surrounding the activated blastocysts after termination of the delay by estradiol-17β (E2). The results suggest that PG synthesis catalyzed by COX-2 is important for localized increased uterine vascular permeability and attachment reaction. The COX-1 gene that was downregulated from the time of attachment reaction on day 4 was again expressed in the mesometrial and anti-mesometrial secondary decidual beds on days 7 and 8. These results suggest that PGs generated by COX-1 are involved in decidualization and/or continued localized endometrial vascular permeability observed during this period. In contrast, the COX-2 gene, expressed at the anti-mesometrial pole on days 4 and 5, switched its expression to the mesometrial pole from day 6 onward. These results suggest that PGs produced at this site by COX-2 are involved in angiogenesis for the establishment of placenta. In the ovariectomized mice, the COX-1 gene was induced in the epithelium by a combined treatment with P4 and E2. However, P4 and/or E2 treatments failed to influence the uterine COX-2 gene. Overall, the results suggest that the uterine COX-1 gene is influenced by ovarian steroids, while the COX-2 gene is regulated by the implanting blastocyst during early pregnancy.

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David Finlay, Antonio J Ruiz-Alcaraz, Christopher Lipina, Stephane Perrier and Calum Sutherland

regulation of IGFBP1 gene expression by insulin is the only one of these genes depend upon mTOR activation ( Band & Posner 1997 , Patel et al. 2002 ). Indeed, although PI 3-kinase signalling appears critical in the regulation of most metabolic genes by

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Alexander Dierks, Urs D Lichtenauer, Simone Sackmann, Ariadni Spyroglou, Igor Shapiro, Marcel Geyer, Jenny Manonopoulou, Martin Reincke, Constanze Hantel and Felix Beuschlein

potassium-induced gene regulation In the first instance, we investigated long-term effects of potassium supplementation on murine adrenal morphology and transcriptional regulation of aldosterone synthase in vivo . Despite the fact that no significant

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Anne Wulf, Marianne G Wetzel, Maxim Kebenko, Meike Kröger, Angelika Harneit, Jennifer Merz and Joachim M Weitzel

maintain appropriate concentrations of functionally active nuclear receptors. As shown in Fig. 1A and B , mGPDH promoter-driven reporter constructs led to a positive regulation of gene expression. A positive regulation of gene expression has been observed

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Elena Ivanova and Gavin Kelsey

genes ( Charalambous et al . 2007 , Frontera et al . 2008 ). The hypothalamus is a key regulator of many endocrine functions and is involved in the regulation of energy balance through its influence on food intake, metabolic rate and body temperature

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A J Tyson-Capper, E A Shiells and S C Robson

DNA-binding domains associated with transcriptional regulation ( Urban et al . 2002 ). PSF contributes to the repression of oncogenic genes and is recruited to activated promoters of specific genes, such as the P450scc gene ( Urban & Bodenburg 2002

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Carolyn M Mitchell, Shane D Sykes, Xin Pan, Kirsty G Pringle, Eugenie R Lumbers, Jonathan J Hirst and Tamas Zakar

in the amnion. There are no significant differences in the decidua. Full colour version of this figure available via http://dx.doi.org/10.1530/JME-12-0211 . Discussion Understanding the regulation of inflammatory genes in the gestational tissues is

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Jarrod Bailey, Alison J Tyson-Capper (née Pollard), Kate Gilmore, Stephen C Robson and G Nicholas Europe-Finner

expression levels. Real-time RT-PCR analysis of two of these genes, PRKCA and CDKN1C, indicated significant up- and down-regulation respectively of their expression in stable cell lines in accordance with the microarray data, and also increased expression in

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Yewei Xing, C Richard Parker, Michael Edwards and William E Rainey

been validated in adrenocortical cells. The functions of these candidates in ACTH regulation of the adrenal gland need further elucidation. Of all the genes upregulated in human FA, one interesting finding is the GNRHR gene. In the previous study, we