An Endocrine-Exocrine Switch in the Activity of the Pancreatic Homeodomain Protein PDX1 through Formation of a Trimeric Complex with PBX1b and MRG1 (MEIS2)

ABSTRACT HOX proteins and some orphan homeodomain proteins form complexes with either PBX or MEIS subclasses of homeodomain proteins. This interaction can increase the binding specificity and transcriptional effectiveness of the HOX partner. Here we show that specific members of both PBX and MEIS subclasses form a multimeric complex with the pancreatic homeodomain protein PDX1 and switch the nature of its transcriptional activity. The two activities of PDX1 are exhibited through the 10-bp B element of the transcriptional enhancer of the pancreatic elastase I gene (ELA1). In pancreatic acinar cells the activity of the B element requires other elements of the ELA1 enhancer; in β-cells the B element can activate a promoter in the absence of other enhancer elements. In acinar cell lines the activity is mediated by a complex comprising PDX1, PBX1b, and MRG1 (MEIS2). In contrast, β-cell lines are devoid of PBX1b and MRG1, so that a trimeric complex does not form, and the β-cell-type activity is mediated by PDX1 without PBX1b and MRG1. The presence of specific nuclear isoforms of PBX and MEIS is precisely regulated in a cell-type-specific manner. The β-cell-type activity can be detected in acinar cells if the B element is altered to retain binding of PDX1 but prevent binding of the PDX1-PBX1b-MRG1 complex. These observations suggest that association with PBX and MEIS partners controls the nature of the transcriptional activity of the organ-specific PDX1 transcription factor in exocrine versus endocrine cells.

[1]  N. M. Brooke,et al.  The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster , 1998, Nature.

[2]  Richard S. Mann,et al.  Control of antennal versus leg development in Drosophila , 1998, Nature.

[3]  M. Waterman,et al.  Members of the Meis1 and Pbx Homeodomain Protein Families Cooperatively Bind a cAMP-responsive Sequence (CRS1) from BovineCYP17 * , 1998, The Journal of Biological Chemistry.

[4]  J. Berthelsen,et al.  The novel homeoprotein Prep1 modulates Pbx–Hox protein cooperativity , 1998, The EMBO journal.

[5]  S. Antonarakis,et al.  Meis1 and pKnox1 bind DNA cooperatively with Pbx1 utilizing an interaction surface disrupted in oncoprotein E2a-Pbx1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Moskow,et al.  AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins , 1997, Molecular and cellular biology.

[7]  T R Bürglin,et al.  Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals. , 1997, Nucleic acids research.

[8]  Hyung Don Ryoo,et al.  Nuclear Translocation of Extradenticle Requires homothorax , which Encodes an Extradenticle-Related Homeodomain Protein , 1997, Cell.

[9]  N. Copeland,et al.  Meis proteins are major in vivo DNA binding partners for wild-type but not chimeric Pbx proteins , 1997, Molecular and cellular biology.

[10]  P. Chambon,et al.  Meis2, a novel mouse Pbx‐related homeobox gene induced by retinoic acid during differentiation of P19 embryonal carcinoma cells , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  R. Stein,et al.  Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene , 1997, Molecular and cellular biology.

[12]  C. Murre,et al.  Pbx raises the DNA binding specificity but not the selectivity of antennapedia Hox proteins , 1997, Molecular and cellular biology.

[13]  M. German,et al.  Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. , 1997, Genes & development.

[14]  S. Rose,et al.  Evolutionary silencing of the human elastase I gene (ELA1). , 1997, Human molecular genetics.

[15]  C. Largman,et al.  The Abd-B-like Hox Homeodomain Proteins Can Be Subdivided by the Ability to Form Complexes with Pbx1a on a Novel DNA Target* , 1997, The Journal of Biological Chemistry.

[16]  P. Gruss,et al.  The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas , 1997, Nature.

[17]  K. Huebner,et al.  Identification of a conserved family of Meis1-related homeobox genes. , 1997, Genome research.

[18]  R. White,et al.  Nucleocytoplasmic localisation of extradenticle protein is spatially regulated throughout development in Drosophila. , 1997, Development.

[19]  Samuel L. Pfaff,et al.  Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells , 1997, Nature.

[20]  William L. Clarke,et al.  Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence , 1997, Nature Genetics.

[21]  N. Copeland,et al.  Identification of a new family of Pbx-related homeobox genes. , 1996, Oncogene.

[22]  H. Kaneto,et al.  The Human Glucokinase Gene β-Cell-Type Promoter: An Essential Role of Insulin Promoter Factor 1/PDX-1 in Its Activation in HIT-T15 Cells , 1996, Diabetes.

[23]  G. Waeber,et al.  Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. , 1996, Molecular endocrinology.

[24]  R. Mann,et al.  Nuclear import of the homeodomain protein Extradenticle in response to Wg and Dpp signalling , 1996, Nature.

[25]  S. Frutiger,et al.  The p48 DNA‐binding subunit of transcription factor PTF1 is a new exocrine pancreas‐specific basic helix‐loop‐helix protein. , 1996, The EMBO journal.

[26]  R. Mann,et al.  Extra specificity from extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins. , 1996, Trends in genetics : TIG.

[27]  C. Murre,et al.  Engrailed and Hox homeodomain proteins contain a related Pbx interaction motif that recognizes a common structure present in Pbx. , 1996, The EMBO journal.

[28]  Q. Lu,et al.  Pbx-1 Hox heterodimers bind DNA on inseparable half-sites that permit intrinsic DNA binding specificity of the Hox partner at nucleotides 3' to a TAAT motif. , 1996, Nucleic acids research.

[29]  L. Brocchieri,et al.  Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus , 1996, Molecular and cellular biology.

[30]  B. Hogan,et al.  PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. , 1996, Development.

[31]  Takuro Nakamura,et al.  Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias , 1996, Nature Genetics.

[32]  Q. Lu,et al.  Selective repression of transcriptional activators by Pbx1 does not require the homeodomain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[33]  M. Montminy,et al.  The pancreatic islet factor STF-1 binds cooperatively with Pbx to a regulatory element in the somatostatin promoter: importance of the FPWMK motif and of the homeodomain , 1995, Molecular and cellular biology.

[34]  R. Mann.  The specificity of homeotic gene function , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[35]  K. Huebner,et al.  Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice , 1995, Molecular and cellular biology.

[36]  C. Murre,et al.  The hexapeptide LFPWMR in Hoxb-8 is required for cooperative DNA binding with Pbx1 and Pbx2 proteins. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Hammer,et al.  Cooperation between elements of an organ-specific transcriptional enhancer in animals , 1995, Molecular and cellular biology.

[38]  W. Rutter,et al.  The Insulin Gene Promoter: A Simplified Nomenclature , 1995, Diabetes.

[39]  I. Rambaldi,et al.  Cooperative interactions between HOX and PBX proteins mediated by a conserved peptide motif , 1995, Molecular and cellular biology.

[40]  Richard S. Mann,et al.  Segmental expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx , 1995, Cell.

[41]  J. Slack.  Developmental biology of the pancreas. , 1995, Development.

[42]  C. Murre,et al.  Localization of Pbx1 transcripts in developing rat embryos , 1995, Mechanisms of Development.

[43]  M. Cleary,et al.  Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. , 1995, Genes & development.

[44]  R. Stein,et al.  Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. , 1995, Development.

[45]  C. Desplan,et al.  Homeodomain Proteins: Cooperating to be different , 1995, Current Biology.

[46]  M. Montminy,et al.  Insulin expression in pancreatic islet cells relies on cooperative interactions between the helix loop helix factor E47 and the homeobox factor STF-1. , 1994, Molecular endocrinology.

[47]  H. Edlund,et al.  Insulin-promoter-factor 1 is required for pancreas development in mice , 1994, Nature.

[48]  R. Krumlauf.  Hox genes in vertebrate development , 1994, Cell.

[49]  Peter A. Lawrence,et al.  Homeobox genes: Their function in Drosophila segmentation and pattern formation , 1994, Cell.

[50]  M. Waterman,et al.  A cAMP-regulatory sequence (CRS1) of CYP17 is a cellular target for the homeodomain protein Pbx1. , 1994, The Journal of biological chemistry.

[51]  J. Grendell.  The pancreas, biology, pathobiology, and disease. 2nd ed , 1994 .

[52]  S. Rose,et al.  An element of the elastase I enhancer is an overlapping bipartite binding site activated by a heteromeric factor. , 1994, The Journal of biological chemistry.

[53]  R. Hammer,et al.  A single element of the elastase I enhancer is sufficient to direct transcription selectively to the pancreas and gut , 1994, Molecular and cellular biology.

[54]  J. Habener,et al.  IDX‐1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. , 1994, The EMBO journal.

[55]  D. Duboule.  Guidebook to the homeobox genes , 1994 .

[56]  C. Rieder,et al.  Greatwall kinase , 2004, The Journal of cell biology.

[57]  H. Ohlsson,et al.  IPF1, a homeodomain‐containing transactivator of the insulin gene. , 1993, The EMBO journal.

[58]  M. Montminy,et al.  Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. , 1993, Molecular endocrinology.

[59]  R. Hammer,et al.  An endocrine-specific element is an integral component of an exocrine-specific pancreatic enhancer. , 1993, Genes & development.

[60]  G. Teitelman.  On the origin of pancreatic endocrine cells, proliferation and neoplastic transformation. , 1993, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[61]  G. Ruvkun,et al.  New motif in PBX genes , 1992, Nature Genetics.

[62]  C B Wollheim,et al.  Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. , 1992, Endocrinology.

[63]  B. Wiedenmann,et al.  An amphicrine pancreatic cell line: AR42J cells combine exocrine and neuroendocrine properties. , 1992, European journal of cell biology.

[64]  M. Cleary,et al.  PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1 , 1991, Molecular and cellular biology.

[65]  P. Lawrence,et al.  Induction across germ layers in Drosophila mediated by a genetic cascade , 1990, Cell.

[66]  David Baltimore,et al.  A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B all , 1990, Cell.

[67]  Michael L. Cleary,et al.  Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor , 1990, Cell.

[68]  O. Hagenbüchle,et al.  The DNA-binding activity of transcription factor PTF1 parallels the synthesis of pancreas-specific mRNAs during mouse development , 1990, Molecular and cellular biology.

[69]  M. Cockell,et al.  Identification of a cell-specific DNA-binding activity that interacts with a transcriptional activator of genes expressed in the acinar pancreas , 1989, Molecular and cellular biology.

[70]  D. J. Shapiro,et al.  A highly sensitive, mixed-phase assay for chloramphenicol acetyltransferase activity in transfected cells. , 1989, Analytical biochemistry.

[71]  P. Schnegelsberg,et al.  XlHbox 8: a novel Xenopus homeo protein restricted to a narrow band of endoderm. , 1989, Development.

[72]  D. Hanahan,et al.  Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[73]  C. Michnoff,et al.  The Cell-Specific Elastase I Enhancer Comprises Two Domains , 1988, Molecular and cellular biology.

[74]  N. L. Le Douarin.  On the origin of pancreatic endocrine cells. , 1988, Cell.

[75]  R. Hammer,et al.  Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice. , 1987, Science.

[76]  R. Palmiter,et al.  Promoter and enhancer elements from the rat elastase I gene function independently of each other and of heterologous enhancers , 1987, Molecular and cellular biology.

[77]  J. Habener,et al.  Multipotential phenotypic expression of genes encoding peptide hormones in rat insulinoma cell lines. , 1987, The Journal of clinical investigation.

[78]  J. Chirgwin,et al.  Isolation of RNA using guanidinium salts. , 1987, Methods in enzymology.

[79]  D. Moore,et al.  Human growth hormone as a reporter gene in regulation studies employing transient gene expression , 1986, Molecular and cellular biology.

[80]  R. Palmiter,et al.  Specific expression of an elastase–human growth hormone fusion gene in pancreatic acinar cells of transgenic mice , 1985, Nature.

[81]  R. Hammer,et al.  Tissue-specific expression of the rat pancreatic elastase I gene in transgenic mice , 1984, Cell.

[82]  D. Melton,et al.  Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs. , 1984, Nucleic acids research.

[83]  R. Roeder,et al.  Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. , 1983, Nucleic acids research.

[84]  E Neumann,et al.  Electric field mediated gene transfer. , 1982, Biochemical and biophysical research communications.

[85]  A. van der Eb,et al.  A new technique for the assay of infectivity of human adenovirus 5 DNA. , 1973, Virology.