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Activin A AND Pax4

Danielle Andrzejewski, Melissa L Brown, Nathan Ungerleider, Amy Burnside, Alan L Schneyer
TGFβ superfamily ligands, receptors, and second messengers, including activins A and B, have been identified in pancreatic islets and proposed to have important roles regulating development, proliferation, and function. We previously demonstrated that Fstl3 (an antagonist of activin activity) null mice have larger islets with β-cell hyperplasia and improved glucose tolerance and insulin sensitivity in the absence of altered β-cell proliferation. This suggested the hypothesis that increased activin signaling influences β-cell expansion by destabilizing the α-cell phenotype and promoting transdifferentiation to β-cells...
July 2015: Endocrinology
Sudhanshu P Raikwar, Nicholas Zavazava
Pluripotent embryonic stem (ES) cells and induced pluripotent stem (iPS) cells recently developed in our laboratory can be used to generate the much needed insulin producing cells (IPCs) for the treatment of type 1 diabetes. However, currently available differentiation protocols generate IPCs at a very low frequency. More importantly, it is difficult to purify the IPCs from the mixed cell population due to the lack of well characterized pancreatic beta cell-specific cell surface markers. Subsequently, multiple studies have been published with limited success...
2013: Methods in Molecular Biology
Maria João Lima, Hilary M Docherty, Yuanxiao Chen, Ludovic Vallier, Kevin Docherty
Protein transduction domains (PTDs), such as the HIV1-TAT peptide, have been previously used to promote the uptake of proteins into a range of cell types, including stem cells. Here we generated pancreatic transcription factors containing PTD sequences and administered these to endoderm enriched mouse embryonic stem (ES) cells under conditions that were designed to mimic the pattern of expression of these factors in the developing pancreas. The ES cells were first cultured as embryoid bodies and treated with Activin A and Bone morphogenetic protein 4 (BMP4) to promote formation of definitive endoderm...
2012: PloS One
Thierry Brun, Kai Hui Hu He, Roberto Lupi, Bernhard Boehm, Anne Wojtusciszyn, Nadine Sauter, Marc Donath, Piero Marchetti, Kathrin Maedler, Benoit R Gauthier
We previously demonstrated that the transcription factor Pax4 is important for beta-cell replication and survival in rat islets. Herein, we investigate Pax4 expression in islets of non-diabetic and diabetic donors, its regulation by mitogens, glucose and the incretin GLP-1 and evaluate its effect on human islet proliferation. Pax4 expression was increased in islets derived from Type 2 diabetic donors correlating with hyperglycaemia. In vitro studies on non diabetic islets demonstrated that glucose, betacellulin, activin A, GLP-1 and insulin increased Pax4 mRNA levels...
February 15, 2008: Human Molecular Genetics
T Brun, D L Duhamel, K H Hu He, C B Wollheim, B R Gauthier
The paired/homeodomain transcription factor Pax4 is essential for islet beta-cell generation during pancreas development and their survival in adulthood. High Pax4 expression was reported in human insulinomas indicating that deregulation of the gene may be associated with tumorigenesis. We report that rat insulinoma INS-1E cells express 25-fold higher Pax4 mRNA levels than rat islets. In contrast to primary beta-cells, activin A but not betacellulin or glucose induced Pax4 mRNA levels indicating dissociation of Pax4 expression from insulinoma cell proliferation...
June 21, 2007: Oncogene
Aline Mamin, Jacques Philippe
Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in beta-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the alpha-cell lines InR1G9 and alphaTC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets...
January 2007: Molecular Endocrinology
Rei Kanno, Takeshi Ogihara, Yasuhiro Igarashi, Yasushi Tanaka, Stuart B Smith, Itaru Kojima, Michael S German, Ryuzo Kawamori, Hirotaka Watada
Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic beta cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located approximately 1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation. This region contains an E box and binding sites for hepatocyte nuclear factor (HNF)-1alpha...
January 2006: Biochimica et Biophysica Acta
Thierry Brun, Isobel Franklin, Luc St-Onge, Anna Biason-Lauber, Eugene J Schoenle, Claes B Wollheim, Benoit R Gauthier
The mechanism by which the beta-cell transcription factor Pax4 influences cell function/mass was studied in rat and human islets of Langerhans. Pax4 transcripts were detected in adult rat islets, and levels were induced by the mitogens activin A and betacellulin. Wortmannin suppressed betacellulin-induced Pax4 expression, implicating the phosphatidylinositol 3-kinase signaling pathway. Adenoviral overexpression of Pax4 caused a 3.5-fold increase in beta-cell proliferation with a concomitant 1.9-, 4-, and 5-fold increase in Bcl-xL (antiapoptotic), c-myc, and Id2 mRNA levels, respectively...
December 20, 2004: Journal of Cell Biology
K Umezawa, A Hiroki, M Kawakami, H Naka, I Takei, T Ogata, I Kojima, T Koyano, T Kowithayakorn, H-S Pang, T-S Kam
We set up a screening system to detect low-molecular-weight compounds that induce insulin expression in pancreatic acinar carcinoma AR42J cells. They can differentiate into insulin-producing cells with neuron-like morphological change when treated with activin A. We employed this morphological change for the screening of beta-cell inducers among various signal transduction inhibitors. As a result, a vinca alkaloid, conophylline, induced neurite formation at 0.1 approximately 0.3 microg/ml in 72 h, like activin A...
October 2003: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Y Q Zhang, H Mashima, I Kojima
Pancreatic AR42J cells possess both exocrine and neuroendocrine properties and convert to insulin-producing cells upon treatment with activin A and hepatocyte growth factor (HGF). We studied changes in the mRNA expression of various transcription factors during the course of differentiation. Among the transcription factors studied, expression levels of Pax4 and neurogenin3 changed significantly. These two factors were not detected in naive cells, whereas their mRNA levels were markedly increased after treatment with activin A and HGF...
February 2001: Diabetes
Y Ueda
Activin A, a member of the TGFbeta superfamily, has many physiological and developmental functions. In pancreatic beta cell cultures, activin promotes cell differentiation and insulin production. The author has found activin increases gene expression of the PAX4, one of the major transcription factors determining pancreatic beta cell differentiation. This effect was mediated, at least in part, by the type IB activin receptor (ALK4). Moreover, the activity of human insulin promoter-reporter system was controlled by PAX4 and its isoform PAX4 delta(G239-P251) in a unique fashion; positively by low concentrations, and negatively by high concentrations of these proteins...
September 1, 2000: FEBS Letters
J Palgi, E Stumpf, T Otonkoski
AR42J is an exocrine pancreatic cell line that has been reported to differentiate towards an endocrine phenotype when stimulated with various growth factors, such as activin A, hepatocyte growth factor (HGF), betacellulin or glucagon-like peptide 1. In our experiments, AR42J-B13 cells differentiated morphologically in response to the growth factor treatment as reported previously. However, they failed to express the insulin gene. We found that the cells did not express several transcription factors known to be found in the beta-cell, including Nkx6...
July 25, 2000: Molecular and Cellular Endocrinology
T Yamaoka, M Itakura
Recent studies have revealed that islet cells differentiate from the epithelial cells of primitive pancreatic ducts during embryogenesis, and can regenerate in response to the loss of islet cells even in adult pancreas. The ability of islet cells to regenerate raises the possibility that impaired and decreased islets of diabetic patients can be restored. In this review, factors regulating islet development including differentiation factors (Shh, activin, follistatin, and TGF alpha), transcriptional factors (PDX1, Isl1, Pax4, Pax6, Nkx2...
March 1999: International Journal of Molecular Medicine
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