The estrogen-related receptor alpha upregulates secretin expressions in response to hypertonicity and angiotensin II stimulation

Osmoregulation via maintenance of water and salt homeostasis is a vital process. In the brain, a functional secretin (SCT) and secretin receptor (SCTR) axis has recently been shown to mediate central actions of angiotensin II (ANGII), including initiation of water intake and stimulation of vasopressin (VP) expression and release. In this report, we provide evidence that estrogen-related receptor α (ERRα, NR3B1), a transcription factor mainly involved in metabolism, acts as an upstream activator of the SCT gene. In vitro studies using mouse hypothalamic cell line N-42 show that ERRα upregulates SCT promoter and gene expression. More importantly, knockdown of endogenous ERRα abolishes SCT promoter activation in response to hypertonic and ANGII stimulations. In mouse brain, ERRα coexpresses with SCT in various osmoregulatory brain regions, including the lamina terminalis and the paraventricular nucleus of the hypothalamus, and its expression is induced by hyperosmotic and ANGII treatments. Based on our data, we propose that both the upregulation of ERRα and/or the increased binding of ERRα to the mouse SCT promoter are two possible mechanisms for the elevated SCT expression upon hyperosmolality and central ANGII stimulation. © 2012 Lee et al.published_or_final_versio

A functional variable number of tandem repeats is located at the 5′ flanking region of the human secretin gene plays a downregulatory role in expression

Secretin is a peptide hormone playing multiple functions in the brain-gut axis. In this report, we investigated, by promoter analysis, the potential function of the variable of tandem repeats (VNTR), located at the 5′ upstream region of the human secretin gene, and we demonstrated for the first time that this VNTR could downregulate transcription of the human secretin gene in a promoter-specific manner. The efficiency of VNTR in silencing the promoter was found to be directly related the number of repetitive units residing within. We also showed the deoxyribonucleic acid sequence as well as the length polymorphism of the VNTR of 76 Chinese individuals. These results collectively suggest that VNTR could potentially be a functional regulator to control the expression of the human secretin gene in different individuals. © 2008 Humana Press.link_to_subscribed_fulltex

Multiple Actions of Secretin in the Human Body

The discovery of secretin initiated the field of endocrinology. Over the past century, multiple gastrointestinal functions of secretin have been extensively studied, and it was discovered that the principal function of this peptide in the gastrointestinal system is to facilitate digestion and to provide protection. In view of the late identification of secretin and the secretin receptor in various tissues, including the central nervous system, the pleiotropic functions of secretin have more recently been an area of intense focus. Secretin is a classical hormone, and recent studies clearly showed secretin's involvement in neural and neuroendocrine pathways, although the neuroactivity and neural regulation of its release are yet to be elucidated. This chapter reviews our current understanding of the pleiotropic actions of secretin with a special focus on the hormonal and neural interdependent pathways that mediate these actions. © 2008 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Signaling mechanisms of secretin receptor

Secretin, a 27-amino acid gastrointestinal peptide, was initially discovered based on its activities in stimulating pancreatic juice. In the past 20 years, secretin was demonstrated to exhibit pleiotropic functions in many different tissues and more importantly, its role as a neuropeptide was substantiated. To carry out its activities in the central nervous system and in peripheral organs, secretin interacts specifically with one known receptor. Secretin receptor, a member of guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) in the secretin/VIP/glucagon subfamily, possesses the characteristics of GPCR with seven conserved transmembrane domains, a relatively large amino-terminal extracellular domain and an intracellular carboxyl terminus. The structural features and signal transduction pathways of the secretin receptor in various tissues are reviewed in this article. © 2006 Elsevier B.V. All rights reserved.link_to_subscribed_fulltex

Localization of small heterodimer partner (SHP) and secretin in mouse duodenal cells

Previous studies have demonstrated the transcriptional repressive property of the atypical nuclear receptor, small heterodimer partner (SHP), on NeuroD. NeuroD is a basic helix-loop-helix transcription factor that has also been shown to be important in modulating secretin gene expression. The present study revealed the activation of the human secretin core promoter by overexpressing NeuroD, and the localization of SHP and secretin-producing cells in mouse duodenal epithelium by immunohistochemical stainings. These results indicated that SHP and secretin are potentially co-expressed and lead us to propose a novel regulatory pathway, in which SHP represses NeuroD's positive regulatory activity on secretin gene. © 2006 New York Academy of Sciences.link_to_subscribed_fulltex

An investigation on p21-activated protein kinase 1 inhibitor, IPA-3, in hepatocellular carcinoma

Poster Session 20 - Pathogenesis of Gastrointestinal and Hepatocellular Carcinomas: abstract no. 4429BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to metastasis and tumor recurrence. However, apart from Sorafenib, there is no proven effective systemic chemotherapy for HCC yet. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is commonly found in HCC, which is coupled with a more aggressive tumor behavior. In this study, we examined the effect of an allosteric inhibitor of PAK1, IPA-3, on hepatocarcinogenesis. METHODS: Human HCC line H2M was treated with various dosages of IPA-3 or ...link_to_OA_fulltextThe 103rd Annual Meeting of the American Association for Cancer Research (AACR 2012), Chicago, IL., 31 March-4 April 2012