1: Biochem Biophys Res Commun. 2005 Aug 12;333(4):1153-9. 

Endocrine pancreatic tissue plasticity in obese humans is associated with
cytoplasmic expression of PBX-1 in pancreatic ductal cells.

Muharram G, Beucher A, Moerman E, Belaich S, Gmyr V, Vandewalle B, Pattou F,
Kerr-Conte J.

Cell Therapy of Diabetes, INSERM ERIT-M 0106, Faculty of Medicine, 1 Place de
Verdun 59045 Lille, France.

In vivo lineage tracing experiments in mice have recently cast doubt on the
potential islet neogenesis from ductal precursors in adult mammals. We examined,
in human obesity, a model for pancreatic endocrine tissue plasticity, the gene
and protein expression of PBX-1-a transcription factor expressed in regenerating
rat ductules and potentially implicated in the pancreatic development, alone or
in association with PDX-1. When comparing gene expression, by quantitative
real-time RT-PCR, in pancreatic exocrine tissue from obese non-diabetic subjects
with increased islet mass, we found that Pbx-1 and Pdx-1 were up-regulated
(5.9+/-1.2 and 2.4+/-0.6 versus non-obese). Immunohistochemistry confirmed PBX-1
over-expression and its cytoplasmic sequestration in ductal cells of obese
subjects, associated with pronounced islet neogenesis (cytokeratin
19/chromogranin A double labeling). cDNA microarray analysis also showed
up-regulation of other genes implicated in islet regeneration, including
betacellulin, laminin, TGFa, NeuroD1, Pax6, substantiating the role of the islet
neogenesis pathway in human obesity.

PMID: 15979049 [PubMed - indexed for MEDLINE]


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2: J Biol Chem. 2000 Sep 8;275(36):27989-99. 

Heterodimeric Pbx-Prep1 homeodomain protein binding to the glucagon gene
restricting transcription in a cell type-dependent manner.

Herzig S, Fuzesi L, Knepel W.

Department of Molecular Pharmacology and Department of Gastroenteropathology,
University of Gottingen, 37075 Gottingen, Germany.

Homeodomain proteins specify developmental pathways and cell-specific gene
transcription whereby proteins of the PBC subclass can direct target gene
specificity of Hox proteins. Proteins encoded by nonclustered homeobox genes
have been shown to be essential for cell lineage differentiation and gene
expression in pancreatic islets. Using specific antiserum in an electrophoretic
mobility shift assay and in vitro transcribed/translated proteins, the nuclear
proteins binding domain B of the G3 enhancer-like element of the glucagon gene
were identified in the present study as heterodimers consisting of the
ubiquitously expressed homeodomain protein Prep1 and the also widely expressed
PBC homeoprotein Pbx (isoform 1a, 1b, or 2). These heterodimeric complexes were
found to bind also to the glucagon cAMP response element and to a newly
identified element termed G5 (from -169 to -140). Whereas the expression of
Prep1 or Pbx forms alone had no effect, coexpression of Pbx1a/1b-Prep1 inhibited
the glucagon promoter when activated by cotransfected Pax6 or another
transcription factor in non-glucagon-producing cells. In contrast, in
glucagon-producing pancreatic islet cells, Pbx-Prep1 had no effect on
GAL4-Pax6-induced mutant glucagon promoter activity or on Pax6-dependent
wild-type glucagon promoter activity. Furthermore, 5'-deletion of G5 enhanced
glucagon promoter activity in a non-glucagon-producing cell line but not in
glucagon-producing islet cells. This study thus identifies a novel target and
Hox-independent function of Pbx-Prep1 heterodimers that, through repression of
glucagon gene transcription in non-glucagon-producing cells, may help to
establish islet cell-specific expression of the glucagon gene.

PMID: 10869353 [PubMed - indexed for MEDLINE]


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