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Conditional Expression of Hepatocyte Nuclear Factor-1B, the Maturity-Onset

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Conditional Expression of Hepatocyte Nuclear Factor-1B, the Maturity-Onset 171 Conditional expression of hepatocyte nuclear factor-1b, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic b-cells Hannah J Welters, Sabine Senkel1, Ludger Klein-Hitpass1, Silke Erdmann1, Heike Thomas1, Lorna W Harries, Ewan R Pearson, Coralie Bingham, Andrew T Hattersley, Gerhart U Ryffel1 and Noel G Morgan Institute of Biomedical and Clinical Science, Peninsula Medical School, Universities of Exeter and Plymouth, Research Way, Plymouth, Devon PL6 8BU,UK 1Institut fu¨r Zellbiologie, Universita¨tsklinikum Essen, D-45122 Essen, Germany (Requests for offprints should be addressed to N G Morgan; Email: [email protected]) Abstract Mutations in the gene encoding hepatocyte nuclear factor apoptosis. Induction of WT HNF1b also inhibited the insulin (HNF)1b result in maturity-onset diabetes of the young- secretory response to nutrient stimuli, membrane depolaris- (MODY)5, by impairing insulin secretory responses and, ation or activation of protein kinases A and C and this possibly, by reducing b-cell mass. The functional role of correlated with a significant decrease in pancrease-duodenum HNF1b in normal b-cells is poorly understood; therefore, in homeobox-1 protein levels. The attenuation of insulin the present study, wild-type (WT) HNF1b, or one of two secretion was, however, dissociated from the inhibition of naturally occurring MODY5 mutations (an activating proliferation and loss of viability, since expression of the mutation, P328L329del, or a dominant-negative form, P328L329del mutant led to a reduced rate of cell A263insGG) were conditionally expressed in the pancreatic proliferation, but failed to induce apoptosis or to alter insulin b-cell line, insulin-1 (INS-1), and the functional conse- secretion. Taken together, the present results suggest that quences examined. Surprisingly, overexpression of the mature rodent b-cells are sensitive to increased expression of dominant-negative mutant did not modify any of the WT HNF1b and they imply that the levels of this protein are functional properties of the cells studied (including insulin tightly regulated to maintain secretory competence and cell secretion, cell growth and viability). By contrast, expression of viability. WT HNF1b was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in Journal of Endocrinology (2006) 190, 171–181 Introduction the functional competence of the pancreatic b-cell and, as a consequence, mutations that lead to altered transcriptional or Maturity-onset diabetes of the young (MODY) is an early enzymatic activity are sufficient to cause b-cell defects and onset form of monogenic type II diabetes, which typically hence diabetes. As yet, the MODY5 gene, HNF1b, has not presents before 25 years (Fajans et al. 2001, Owen & been ascribed a clear role in pancreatic b-cells. Hattersley 2001) and is inherited in an autosomal dominant HNF1a and 1b are nuclear transcription factors of the manner. MODY patients have a primary defect at the level of homeodomain family. Their genes are located on different the b-cell caused by mutations in specific genes. Most of these chromosomes in man, but the two may have arisen by an genes encode transcription factors, including hepatocyte original gene duplication event during evolution (Bach et al. nuclear factor-(HNF)4a (MODY1) (Yamagata et al. 1996a), 1991). The proteins share a high degree of sequence HNF1a (MODY3) (Yamagata et al. 1996b), pancreas- homology, but are most divergent within the C-terminal duodenum homeobox-1 (PDX-1; MODY4) (Stoffers et al. transactivation domain. HNF1a and -1b bind to the same 1997), HNF1b (MODY5) (Horikawa et al. 1997, Nishigori DNA consensus sequence and they can interact with this et al. 1998, Lindner et al. 1999, Bingham et al. 2000, Bingham region either as homodimers or as an HNF1a/1b hetero- & Hattersley 2004) and neuroD1/Beta2 (MODY6) (Malecki dimer (Mendel et al. 1991, Bach & Yaniv 1993, Cereghini et al. 1999). The exception is MODY2, which is caused by 1996). mutations in the glucokinase gene (Froguel et al. 1993). In Despite the apparent similarities between HNF1a and -1b, most cases, the MODY genes are known to be important for it is likely that they undertake distinct functional roles within Journal of Endocrinology (2006) 190, 171–181 DOI: 10.1677/joe.1.06768 0022–0795/06/0190–171 q 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 02:56:21PM via free access 172 H J WELTERS and others $ Function of HNF1b in pancreatic b-cells the b-cell, as evidenced by the different phenotypes seen revealed that alterations in glucose homeostasis can occur in in MODY3 and MODY5 patients. Patients with mutations RIP-Cre mice that are unrelated to changes in the gene of in HNF1b have an impaired insulin secretory response interest (Lee et al. 2006). to glucose and sulphonylureas (Nishigori et al. 1998, Bingham In order to investigate the function of HNF1b in mature et al. 2000, Ryffel 2001, Pearson et al. 2004) and they exhibit a b-cells without the potential complications arising from RIP- progressive loss in basal insulin secretion, suggesting a decline Cre-recombinase-mediated knockout, we have used a clonal in b-cell mass. In contrast, MODY3 patients retain a robust b-cell line (INS-1) to conditionally express either wild-type insulin secretory response to sulphonylureas despite the (WT) HNF1b or one of two naturally occurring mutants attenuation of glucose-induced insulin secretion (Pearson identified in patients with MODY5 (A263insGG and et al. 2003, 2004). Thus, it seems likely that HNF1a and -1b P328L329del). The mutation P328L329del (abbreviated to exert differential effects in the b-cell and that the latter may P328del) leads to the synthesis of a protein having a severely regulate both secretory competence and cell viability. truncated transactivation domain, but that retains the DNA Previous studies have established that HNF1a is expressed binding and dimerisation domains (Fig. 1) (Bingham et al. in mature b-cells and that it promotes the transcription of a 2000). From studies in HeLa cells, P328del has been reported range of genes in these cells. These include several genes that to possess increased transcriptional activity compared with are critical for the maintenance of the b-cell phenotype, such WT HNF1b (Wild et al. 2000), although examination of the as Glut-2, PDX-1, L-type pyruvate kinase and possibly profile of genes that are up-regulated in response to the insulin (Wang et al. 1998, Ben-Shushan et al. 2001, Shih et al. expression of this mutant in INS-1 cells suggests that it may be 2001). HNF1a may also be required for the proliferation of less active than the WT (Thomas et al. 2004). The A263insGG b-cells as it has been demonstrated to regulate genes involved (A263ins) mutant has no transactivation domain and a in control of the cell cycle, such as cyclin E, p27 and insulin- truncated DNA-binding domain that is non-functional like growth factor-I (Wobser et al. 2002, Yang et al. 2002). (Senkel et al. 2005). However, A263ins can still form dimers In contrast, little is known about the role of HNF1b in with WT HNF1b and this has been suggested to result in b-cells. Homozygous HNF1b knockout mice are non-viable, dominant-negative activity against the native form in a variety with death occurring soon after implantation of the embryo of cell types, including the pancreatic b-cell line MIN6 (7$5 embryo days in mice) (Barbacci et al. 1999, Coffinier (Nishigori et al. 1998, Tomura et al. 1999, Bai et al. 2002). et al. 1999), making the function of HNF1b difficult to study using whole animal knockout approaches. In experiments where HNF1b has been selectively deleted in mature mouse b-cells (using Cre-recombinase expressed under the control Materials and Methods of the insulin promoter (RIP-Cre)), there was evidence of Cell culture impaired glucose tolerance and reduced insulin secretion. These are correlated with alterations in the functional activity Pancreatic b-cell lines (INS-1) that conditionally express of other b-cell transcription factors such that PDX-1 and human WT HNF1b or one of two mutant forms, designated HNF1a were increased and HNF4a decreased (Wang et al. P328del or A263ins, were used in these experiments. These 2004). These results suggest that the expression of HNF1b cell lines were recently described in detail by Thomas et al. may be required to maintain the differentiation state and (2004) but, briefly, cDNAs encoding WTor the mutant forms functional activity of mature b-cells (Coffinier et al. 1999, of HNF1b were cloned downstream of the Tet operator in Wang et al. 2004). However, the experiments must be the plasmid pcDNA5/FRT/TO. This plasmid was integrated interpreted with caution, since it has subsequently been by site-directed Flp recombination into the insulinoma cell Dimerisation DNA binding Transactivation WT HNF1β 1 32 88 176 231 313 557 A263insGG 264 P328L329del 356 Figure 1 Structure of the HNF1b protein. Schematic diagram of HNF1b protein structure showing wild-type and the two truncated proteins encoded by MODY5 mutations. The native protein contains a dimerisation domain, a DNA-binding domain and a transactivation domain. The numbers refer to the amino acid positions in WT HNF1b. Journal of Endocrinology (2006) 190, 171–181 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 02:56:21PM via free access Function of HNF1b in pancreatic b-cells $ H J WELTERS and others 173 clone INS1-Flp-In-T-Rex. Stable cell lines containing 8 mM probe in a total reaction volume of 20 ml on the TaqMan the HNF1b gene were obtained by hygromycin selection.
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