DOCSLIB.ORG

PDX1 and ISL1 Differentially Coordinate with Epigenetic Modifications to Regulate Insulin Gene Expression in Varied Glucose Concentrations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PDX1 and ISL1 Differentially Coordinate with Epigenetic Modifications to Regulate Insulin Gene Expression in Varied Glucose Concentrations Accepted Manuscript PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations Weiping Wang, Qiong Shi, Ting Guo, Zhe Yang, Zhuqing Jia, Ping Chen, Chunyan Zhou PII: S0303-7207(16)30067-3 DOI: 10.1016/j.mce.2016.03.019 Reference: MCE 9454 To appear in: Molecular and Cellular Endocrinology Received Date: 1 November 2015 Revised Date: 26 February 2016 Accepted Date: 15 March 2016 Please cite this article as: Wang, W., Shi, Q., Guo, T., Yang, Z., Jia, Z., Chen, P., Zhou, C., PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations, Molecular and Cellular Endocrinology (2016), doi: 10.1016/j.mce.2016.03.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Regular paper PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations Weiping Wang, Qiong Shi, Ting Guo, Zhe Yang, Zhuqing Jia, Ping Chen, Chunyan Zhou* Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, 38 Xue Yuan Road, Beijing 100191, China *Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, MANUSCRIPTPeking University, 38 Xue Yuan Road, Beijing 100191, China, Phone: 86-10-82802417. Fax: 86-10-62015582. E-mail: [email protected] ACCEPTED 1 ACCEPTED MANUSCRIPT ABSTRACT The mechanism of insulin gene transcription control in response to glucose concentration is poorly defined. The islet-restricted transcription factors PDX1 and ISL1 interact with BETA2, activating insulin gene expression. However, their contribution and hierarchical organization in insulin expression control based on glucose concentration remain unknown. We investigated PDX1 and ISL1 regulation of insulin gene expression in pancreatic β cells cultured in normal (5 mM/L) and high (25 mM/L) glucose conditions. ISL1 interacted with BETA2 to maintain basic insulin gene transcriptional activity under normal glucose. The ISL1-recruited cofactors SET9 and JMJD3 facilitated insulin gene histone modifications under normal glucose. In high-glucose concentrations, PDX1 formed a complex with BETA2 to enhance insulin gene expression. PDX1 also recruited SET9 and JMJD3 to promote the activation of histone modulation on the insulin promoter. This is the first evidence transcription factors orchestrate epigenetic modifications to control insulin gene expression based on glucose concentration. MANUSCRIPT Keywords: Insulin, PDX1, ISL1, Glucose, SET9, JMJD3 ACCEPTED 2 ACCEPTED MANUSCRIPT 1. Introduction Insulin is one of the critical hormones for regulating blood glucose levels and is produced exclusively by pancreatic β cells. The insulin ( INS ) gene was first cloned and sequenced in 1980, opening up a new field of research on the mechanisms controlling its expression (Bell, Pictet, Rutter et al., 1980). To date, more than 40 regulatory transcription factors of insulin gene expression have been identified (Melloul, Marshak and Cerasi, 2002,Hay and Docherty, 2006). However, the circumstances under which these factors play their roles in regulating insulin gene transcription remain unclear. The islet-restricted transcription factors PDX1 (pancreatic and duodenal homeobox 1), ISL1 (insulin gene enhancer binding protein, islet factor 1), and BETA2 (beta cell E-box transcription factor 2) bind to the A3/A4 and E2 boxes located between 0 and -410 bp upstream of the transcription start site in the rat insulin I promoter (RIP1) (Le Lay and Stein, 2006,Karlsson, Thor, Norberg et al., 1990,Ohlsson, Karlsson and Edlund, 1993). MANUSCRIPTThis cis -acting regulatory sequence is essential for glucose regulation of insulin gene expression (Melloul, Ben-Neriah and Cerasi, 1993); glucose is the central regulator of β cell function and insulin gene expression (Nielsen, Welsh, Casadaban et al., 1985,Evans-Molina, Garmey, Ketchum et al., 2007). PDX1, a master regulator of insulin gene transcription, has been implicated in glucose regulation of insulin gene transcription. PDX1 interacts with histone acetyltransferase p300 to hyperacetylate histone H4 on the insulin gene promoter in response to high glucose concentrations (Mosley, Corbett and Ozcan, 2004). In addition to PDX1, ISL1, a LIM homeodomain protein, also binds to the A3/4 box ofACCEPTED the insulin promoter. As a key transcription factor, ISL1 is not only involved in insulin gene regulation (Peng, Wang, Meng et al., 2005,Zhang, Wang, Guo et al., 2009), but also in cell fate specification and embryonic development (Thor, Ericson, Brannstrom et al., 1991,Wilfinger, Arkhipova and Meyer, 2013). However, whether ISL1 is involved in glucose regulation of insulin gene expression remains unclear. 3 ACCEPTED MANUSCRIPT Intriguingly, previous research has revealed that both PDX1 and ISL1 interact with BETA2, a bHLH transcription factor that binds to the E2 box of the insulin promoter, to activate insulin gene expression (Zhang et al., 2009,Ohneda, Mirmira, Wang et al., 2000). However, no light has been shed on the detailed mechanism underlying how PDX1 and ISL1 influence insulin gene expression under different physical conditions, such as blood glucose levels. Whether the activation of insulin gene expression involves the occurrence of a similar or differing activation effect, or even a competitive effect, remains to be elucidated. In the present study, we explored the molecular mechanism underlying the function of PDX1 and ISL1 in regulating insulin gene expression in response to environmental glucose stimuli. Recent studies have reported increasingly complicated modes of insulin gene regulation in pancreatic islet β cells, which not only involve traditional transcription regulation such as protein–protein and protein–DNA interactions, but also epigenetic modification (Moon, Han, Kim et al., 2014,Qiu, Guo, Huang et al., 2002,Ramalingam, Lu, Hudmon et al., 2014). Gain of histone H3 trimethylated at lysine 4 (H3K4me3) and loss of H3K27me3 on the gene promotersMANUSCRIPT are essential for inducing heterochromatin to euchromatin formation and gene transcription activity (Del Rizzo and Trievel, 2014,Estaras, Fueyo, Akizu et al., 2013). SET9 is an islet-enriched histone H3 K4–specific methyltransferase that enhances PDX1 transcription activity on insulin gene regulation (Francis, Chakrabarti, Garmey et al., 2005). Our recent research has also shown that SET9 functions not only as a histone methyltransferase that increases histone H3 K4 trimethylation on the cyclin D1 promoter region, but also as an adaptor to bridge ISL1 and PDX1 in pancreatic islet β cells (Yang, Zhang, Lu et al., 2015). As a key H3K27me3 demethylase, JMJD3 plays an important role in regulating geneACCEPTED expression in response to environmental signaling stimuli (He, Kim, Kim et al., 2015). We have identified a number of ISL1- or PDX1-interacting proteins by mass spectrometry in pancreatic islet β cells (Yang et al., 2015). Among these factors, we found that SET9 and JMJD3 could be potential candidate epigenetic modifiers. Hence, we investigated whether ISL1 or PDX1 could affect insulin gene transcription in different glucose concentrations not only through traditional 4 ACCEPTED MANUSCRIPT transcription regulation, but also in association with epigenetic modification. In the present study, we demonstrate that ISL1 interacts with BETA2 to maintain basic insulin gene transcriptional activity in normal glucose conditions. In high-glucose conditions, PDX1 forms a complex with BETA2 to enhance insulin gene expression. As cofactors of ISL1 or PDX1, SET9 and JMJD3 facilitate insulin gene histone modification under different glucose conditions. These observations delineate a novel and precise insulin gene regulation pattern in response to glucose signals. Our study provides the first evidence that transcription factors orchestrate epigenetic modifications for proper control of insulin gene expression in response to environmental signaling stimuli. 2. Materials and Methods 2.1 Diabetes animal model and rat pancreatic islet isolation The animal experiments were performed in accordance with the ethical principles and guidelines for scientific experiments on animals of the Swiss Academy of Medical Sciences (1995). The Animal Care andMANUSCRIPT Use Committee of Peking University approved all protocols (LA 2010-066). Db/db mice (14–16 weeks old), which are homozygous for the db gene and exhibit an obese and diabetic phenotype, were used for the type 2 diabetes animal model. Db/m mice, which are heterozygous for the db gene and exhibit a non-diabetic, normal phenotype, were used as controls to the db/db mice. The mice were anesthetized with 5 mg/100 g body weight sodium pentobarbital, and the pancreatic tissues were removed. RNA was prepared from these tissues and used for real-time
Load more

Recommended publications
  • Roles and Regulation of Transcription Factor Mafa in Islet Β-Cells
    Endocr. J./ S. ARAMATA et al.: INSULIN TRANSCRIPTION AND MafA doi: 10.1507/endocrj.KR-101 REVIEW Roles and Regulation of Transcription Factor MafA in Islet β-cells * SHINSAKU ARAMATA, SONG-IEE HAN AND KOHSUKE KATAOKA Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan ＊Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan. Released online August 30, 2007 Correspondence to: Kohsuke KATAOKA, Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan Abstract. Insulin is a critical hormone in the regulation of blood glucose levels. It is produced exclusively by pancreatic islet β-cells. β-cell-enriched transcription factors, such as Pdx1 and Beta2, have dual roles in the activation of the insulin gene promoter establishing β-cell-specific insulin expression, and in the regulation of β-cell differentiation. It was shown that MafA, a β-cell-specific member of the Maf family of transcription factors, binds to the conserved C1/RIPE3b element of the insulin promoter. The Maf family proteins regulate tissue-specific gene expression and cell differentiation in a wide variety of tissues. MafA acts synergistically with Pdx1 and Beta2 to activate the insulin gene promoter, and mice with a targeted deletion of mafA develop age-dependent diabetes. MafA also regulates genes involved in β-cell function such as Glucose transporter 2, Glucagons-like peptide 1 receptor, and Prohormone convertase 1/3. The abundance of MafA in β-cells is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress.
    [Show full text]
  • Rb and P53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors
    Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Title: Rb and p53 execute distinct roles in the development of pancreatic neuroendocrine tumors 2 Running Title: Roles of Rb and p53 in pancreatic neuroendocrine tumors 3 4 1Yuki Yamauchi, 1,2Yuzo Kodama, 1Masahiro Shiokawa, 1Nobuyuki Kakiuchi, 1Saiko Marui, 5 1Takeshi Kuwada, 1Yuko Sogabe, 1Teruko Tomono, 1Atsushi Mima, 1Toshihiro Morita, 1Tomoaki 6 Matsumori, 1Tatsuki Ueda, 1Motoyuki Tsuda, 1Yoshihiro Nishikawa, 1Katsutoshi Kuriyama, 7 1Yojiro Sakuma, 1Yuji Ota, 1Takahisa Maruno, 1Norimitsu Uza, 2Atsuhiro Masuda, 3Hisato 8 Tatsuoka, 3Daisuke Yabe, 4Sachiko Minamiguchi, 5Toshihiko Masui, 3Nobuya Inagaki, 5Shinji 9 Uemoto, 1,6Tsutomu Chiba, and 1Hiroshi Seno 10 11 1Department of Gastroenterology and Hepatology, Kyoto University Graduate School of 12 Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 13 2Department of Gastroenterology, Kobe University Graduate School of Medicine, 7-5-1 14 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. 15 3Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of 16 Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 17 4Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, 54 18 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 1 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes
    Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes Sevda Gheibi *, Tania Singh, Joao Paulo M.C.M. da Cunha, Malin Fex and Hindrik Mulder * Unit of Molecular Metabolism, Lund University Diabetes Centre, Jan Waldenströms gata 35; Box 50332, SE-202 13 Malmö, Sweden; [email protected] (T.S.); [email protected] (J.P.M.C.M.d.C.); [email protected] (M.F.) * Correspondence: [email protected] (S.G.); [email protected] (H.M.) Supplementary Table 1. Transcription factors associated with development of the pancreas. Developmental Gene Aliases Function Ref. Stage SRY-Box Transcription Factor Directs the primitive endoderm SOX17 DE, PFE, PSE [1] 17 specification. Establishes lineage-specific transcriptional programs which leads DE, PFE, PSE, Forkhead Box A2; Hepatocyte to proper differentiation of stem cells FOXA2 PMPs, EPs, [2] Nuclear Factor 3-β into pancreatic progenitors. Regulates Mature β-cells expression of PDX1 gene and aids in maturation of β-cells A pleiotropic developmental gene which regulates growth, and Sonic Hedgehog Signaling differentiation of several organs. SHH DE [3] Molecule Repression of SHH expression is vital for pancreas differentiation and development Promotes cell differentiation, proliferation, and survival. Controls C-X-C Motif Chemokine the spatiotemporal migration of the Receptor 4; Stromal Cell- CXCR4 DE angioblasts towards pre-pancreatic [4] Derived Factor 1 Receptor; endodermal region which aids the Neuropeptide Y3 Receptor induction of PDX1 expression giving rise to common pancreatic progenitors Crucial for generation of pancreatic HNF1 Homeobox B HNF1B PFE, PSE, PMPs multipotent progenitor cells and [5] Hepatocyte Nuclear Factor 1-β NGN3+ endocrine progenitors Master regulator of pancreatic organogenesis.
    [Show full text]
  • The Role of Hes1 in Pancreas Development Expression, Interdependancy and Notch Signalling
    FACULTY OF SCIENCE UNIVERSITY OF COPENHAGEN PhD thesis Cand.scient. Rasmus Klinck Department of Beta Cell Regeneration, Hagedorn Research Institute, and The PhD School of Science, Faculty of Science, University of Copenhagen, Denmark. The role of Hes1 in pancreas development Expression, Interdependancy and Notch signalling. Academic Advisors Dr. Olaf Nielsen, Department of Biology, Faculty of Science, University of Copenhagen – Denmark Dr. Mette C. Jørgensen, Department of Beta Cell Regeneration, Hagedorn Research Institute Denmark Submitted: 31/05/11 Cover picture: e10.5 mouse embryo expressing EGFP under the control of the Hes1 promoter manually stitched together from 15 complete image stacks. 2 Preface This Ph.D. thesis is based on experimental work performed in the Department of β Cell Regeneration at the Hagedorn Research Institute, Gentofte, Denmark from January 2008 to December 2010. The faculty supervisor on the project was Professor Olaf Nielsen, Department of Genetics, Faculty of Science, University of Copenhagen, and the project supervisor was Mette Christine Jørgensen, Ph.D., Chemist, Department of Beta Cell Regeneration at the Hagedorn Research Institute. This thesis is submitted in order to meet the requirements for obtaining a Ph.D. degree at the Faculty of Science, University of Copenhagen. The thesis is built around three scientific Manuscripts: Manuscript I: “A BAC transgenic Hes1-EGFP reporter reveals novel expression domains in mouse embryos” Submitted to Gene Expression Patterns Rasmus Klinck1, Ernst-Martin Füchtbauer2, Jonas Ahnfelt-Rønne1, Palle Serup1,Jan Nygaard Jensen1, Ole Dragsbæk Madsen1, Mette Christine Jørgensen1 1Department of Beta Cell Regeneration, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark .2Department of Molecular Biology, Aarhus University, C.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis Reveals Molecular Subtypes of Pancreatic Cancer
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 17), pp: 28990-29012 Research Paper Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer Nitish Kumar Mishra1 and Chittibabu Guda1,2,3,4 1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA 2Bioinformatics and Systems Biology Core, University of Nebraska Medical Center, Omaha, NE, 68198, USA 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA 4Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA Correspondence to: Chittibabu Guda, email: [email protected] Keywords: TCGA, pancreatic cancer, differential methylation, integrative analysis, molecular subtypes Received: October 20, 2016 Accepted: February 12, 2017 Published: March 07, 2017 Copyright: Mishra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients.
    [Show full text]
  • Establishment of a Long-Term Stable Β-Cell Line and Its
    www.nature.com/scientificreports OPEN Establishment of a long‑term stable β‑cell line and its application to analyze the efect of Gcg expression on insulin secretion Satsuki Miyazaki1, Fumi Tashiro1, Takashi Tsuchiya2, Kazuki Sasaki2,4 & Jun‑ichi Miyazaki3* A pancreatic β‑cell line MIN6 was previously established in our lab from an insulinoma developed in an IT6 transgenic mouse expressing the SV40 T antigen in β‑cells. This cell line has been widely used for in vitro analysis of β‑cell function, but tends to lose the mature β‑cell features, including glucose‑ stimulated insulin secretion (GSIS), in long‑term culture. The aim of this study was to develop a stable β‑cell line that retains the characteristics of mature β‑cells. Considering that mice derived from a cross between C3H and C57BL/6 strains are known to exhibit higher insulin secretory capacity than C57BL/6 mice, an IT6 male mouse of this hybrid background was used to isolate insulinomas, which were independently cultured. After 7 months of continuous culturing, we obtained the MIN6‑CB4 β‑cell line, which stably maintains its GSIS. It has been noted that β‑cell lines express the glucagon (Gcg) gene at certain levels. MIN6‑CB4 cells were utilized to assess the efects of diferential Gcg expression on β‑cell function. Our data show the functional importance of Gcg expression and resulting basal activation of the GLP‑1 receptor in β‑cells. MIN6‑CB4 cells can serve as an invaluable tool for studying the regulatory mechanisms of insulin secretion, such as the GLP‑1/cAMP signaling, in β‑cells.
    [Show full text]
  • Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed
    Page 1 of 58 Diabetes DB16-0887 Mafa enables Pdx1 to effectively convert pancreatic islet progenitors and committed islet ααα-cells into βββ-cells in vivo Taka-aki Matsuoka1,＊＊＊, Satoshi Kawashima1, Takeshi Miyatsuka1,2, Shugo Sasaki1, Naoki Shimo1, Naoto Katakami1, Dan Kawamori1, Satomi Takebe1, Pedro L. Herrera3, Hideaki Kaneto4, Roland Stein5, Iichiro Shimomura1 1 Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan 2 Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan 3 Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, CH-1211 Geneva 4, Switzerland 4 Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Okayama, Japan 5 Department of Molecular Physiology & Biophysics, Vanderbilt University Medical School, 723 Light Hall, Nashville, TN 37232, U.S.A. ＊Corresponding author. Address: 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Tel: 81-6-6879-3743 Fax: 81-6-6879-3739 e-mail: [email protected] Key words: islet α cells, β cells, transdifferentiation, Mafa, Pdx1, diabetes - 1 - Diabetes Publish Ahead of Print, published online February 21, 2017 Diabetes Page 2 of 58 Abstract Among the therapeutic avenues being explored for replacement of the functional islet β-cell mass lost in Type 1 diabetes (T1D), reprogramming of adult cell types into new β-cells has been actively pursued. Notably, mouse islet α-cells will transdifferentiate into β-cells under conditions of near β-cell loss, a condition similar to T1D. Moreover, human islet α-cells also appear to poised for reprogramming into insulin+ cells.
    [Show full text]
  • Beta Cell Adaptation to Pregnancy Requires Prolactin Action on Both
    www.nature.com/scientificreports OPEN Beta cell adaptation to pregnancy requires prolactin action on both beta and non‑beta cells Vipul Shrivastava1, Megan Lee1, Daniel Lee1, Marle Pretorius1, Bethany Radford1, Guneet Makkar1 & Carol Huang1,2,3* Pancreatic islets adapt to insulin resistance of pregnancy by up regulating β‑cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/−), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling afects β‑cell development, to understand β‑cell‑specifc efect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from β‑cells. Here, we found that β‑cell‑specifc Prlr reduction in adult mice led to elevated blood glucose, lowed β‑cell mass and blunted in vivo glucose‑stimulated insulin secretion during pregnancy. When we compared gene expression profle of islets from transgenic mice with global (Prlr+/−) versus β‑cell‑specifc Prlr reduction (βPrlR+/−), we found 95 diferentially expressed gene, most of them down regulated in the Prlr+/− mice in comparison to the βPrlR+/− mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/− mice are more vulnerable to glucolipotoxicity‑induced apoptosis than islets from pregnant βPrlR+/− mice. These observations suggest that down regulation of prolactin action during pregnancy in non‑β‑cells secondarily and negatively afect β‑cell gene expression, and increased β‑cell susceptibility to external insults.
    [Show full text]
  • Retinoblastoma Tumor Suppressor Protein in Pancreatic Progenitors Controls Α- and Β-Cell Fate
    Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate Erica P. Caia,b, Xiaohong Wuc, Stephanie A. Schroera, Andrew J. Eliad,e, M. Cristina Nostroa,f, Eldad Zacksenhausa, and Minna Wooa,b,e,g,1 aToronto General Research Institute and fMcEwen Centre for Regenerative Medicine, University Health Network, Toronto, ON, Canada M5G 1L7; bInstitute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8; cThe First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China; dCampbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2M9; eDepartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9; and gDivision of Endocrinology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada M5G 2C4 Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON, Canada, and approved July 16, 2013 (received for review February 20, 2013) Pancreatic endocrine cells expand rapidly during embryogenesis apoptosis (15), in a highly cell-specific and context-dependent by neogenesis and proliferation, but during adulthood, islet cells manner (16, 17). Although Rb is critical in regulating cell cycle have a very slow turnover. Disruption of murine retinoblastoma entry in proliferating cells, its role in postmitotic cells is more tumor suppressor protein (Rb) in mature pancreatic β-cells has limited. For example, Rb deficiency in proliferating myoblasts a limited effect on cell proliferation. Here we show that deletion induces increased proliferation and apoptosis (18), whereas fi fi of Rb during embryogenesis in islet progenitors leads to an in- Rb de ciency in postmitotic muscle bers does not lead to any crease in the neurogenin 3-expressing precursor cell population, defects (19).
    [Show full text]
  • ID1 Mediates Escape from TGF-Β Tumor Suppression in Pancreatic Cancer
    Author Manuscript Published OnlineFirst on October 3, 2019; DOI: 10.1158/2159-8290.CD-19-0529 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ID1 mediates escape from TGF-β tumor suppression in pancreatic cancer Yun-Han Huang1,2,3, Jing Hu1, Fei Chen1, Nicolas Lecomte4, Harihar Basnet1, Charles J. David1,10, Matthew D. Witkin5, Peter J. Allen6, Steven D. Leach4,6,7,9, Travis J. Hollmann7,8, Christine A. Iacobuzio-Donahue4,7,8, and Joan Massagué1* 1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065 2Weill Cornell/Sloan Kettering/Rockefeller Tri-Institutional MD-PhD Program, New York, NY 10065 3Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY 10065 4The David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 5Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065 6Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065 7Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065 8Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 9Present address: Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, 1 Rope Ferry Road, Hanover, NH 03755-1404 10Present address: Tsinghua University School of Medicine, Department of Basic Sciences, Medical Sciences Building D106, Haidian District, Beijing, China, 100084 Running title: ID1 mediates escape from TGF-β tumor suppression in PDA Keywords: TGF-β, pancreatic cancer, ID1, tumor suppression, EMT Financial support: National Cancer Institute grants R01-CA34610 (JM) and P30-CA008748 (MSKCC), and Predoctoral Fellowship F30-CA203238 (YH).
    [Show full text]
  • Newly Identified Aspects of Tumor Suppression by RB
    Disease Models & Mechanisms 4, 581-585 (2011) doi:10.1242/dmm.008060 AT A GLANCE Newly identified aspects of tumor suppression by RB Patrick Viatour1,2,3 and Julien Sage1,2 The retinoblastoma (RB) tumor suppressor belongs to a interactions with E2F transcription factors (Chinnam and Goodrich, 2011; Knudsen and Knudsen, 2008). In this article and cellular pathway that plays a crucial role in restricting the the accompanying poster, we review recent evidence indicating that G1-S transition of the cell cycle in response to a large RB acts as a molecular adaptor at the crossroads of multiple number of extracellular and intracellular cues. Research pathways, depending on the cellular context. We also discuss the in the last decade has highlighted the complexity of idea that intact RB function might in some cases promote the early regulatory networks that ensure proper cell cycle steps of tumorigenesis, a provocative possibility for the first- progression, and has also identified multiple cellular identified tumor suppressor. functions beyond cell cycle regulation for RB and its two The RB pathway in cancer family members, p107 and p130. Here we review some Mutations targeting the RB pathway are almost universal in cancer, of the recent evidence pointing to a role of RB as a but different components of this pathway are selectively affected molecular adaptor at the crossroads of multiple in distinct cancer types (see ‘RB mutations in human cancers’ pathways, ensuring cellular homeostasis in different section of the poster). Events that affect upstream members of the contexts. In particular, we discuss the pro- and anti- pathway (e.g.
    [Show full text]
  • Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet A-Cells Into B-Cells in Vivo
    Diabetes Volume 66, May 2017 1293 Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet a-Cells Into b-Cells In Vivo Taka-aki Matsuoka,1 Satoshi Kawashima,1 Takeshi Miyatsuka,1,2 Shugo Sasaki,1 Naoki Shimo,1 Naoto Katakami,1 Dan Kawamori,1 Satomi Takebe,1 Pedro L. Herrera,3 Hideaki Kaneto,4 Roland Stein,5 and Iichiro Shimomura1 Diabetes 2017;66:1293–1300 | DOI: 10.2337/db16-0887 Among the therapeutic avenues being explored for re- including coronary and renal disease. A variety of innova- placement of the functional islet b-cell mass lost in tive approaches are being explored to produce b-cells from type 1 diabetes (T1D), reprogramming of adult cell types embryonic stem cells (1,2) and adult cell types (3–5). A into new b-cells has been actively pursued. Notably, supposition in these efforts involves producing conditions mouse islet a-cells will transdifferentiate into b-cells un- that correctly regulate the transcription factor networks der conditions of near b-cell loss, a condition similar to required in programming pancreatic progenitor cells into ISLET STUDIES a T1D. Moreover, human islet -cells also appear to poised b-cells and subsequently controlling mature islet cell func- for reprogramming into insulin-positive cells. Here we tion. These include transcription factors like Pdx1 (6–10), have generated transgenic mice conditionally expressing which is essential in the formation of early pancreatic ep- the islet b-cell–enriched Mafa and/or Pdx1 transcription ithelium, developing b-cells and adult islet b-cells, as well factors to examine their potential to transdifferentiate as neurogenin 3 (Ngn3) (11–13), which is required during embryonic pan–islet cell Ngn3-positive progenitors and embryogenesis for specification of all islet cell types (i.e., the later glucagon-positive a-cell population into b-cells.
    [Show full text]