The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1

Details

Serval ID
serval:BIB_ABB6EEA8A066
Type
Article: article from journal or magazin.
Collection
Publications
Title
The diabetes-linked transcription factor Pax4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1
Journal
Hum Mol Genet
Author(s)
Brun T., Hu He K. H., Lupi R., Boehm B., Wojtusciszyn A., Sauter N., Donath M., Marchetti P., Maedler K., Gauthier B. R.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Publication state
Published
Issued date
2008
Volume
17
Number
4
Pages
478-89
Language
english
Notes
Brun, Thierry
Hu He, Kai Hui
Lupi, Roberto
Boehm, Bernhard
Wojtusciszyn, Anne
Sauter, Nadine
Donath, Marc
Marchetti, Piero
Maedler, Kathrin
Gauthier, Benoit R
eng
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
England
Hum Mol Genet. 2008 Feb 15;17(4):478-89. doi: 10.1093/hmg/ddm325. Epub 2007 Nov 7.
Abstract
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. Glucose-induced Pax4 expression was abolished by the inhibitors LY294002, PD98050 or H89. Surprisingly, increases in Pax4 expression did not prompt a surge in human islet cell replication. Furthermore, expression of the proliferation marker gene Id2 remained unaltered. Adenoviral-mediated expression of human Pax4 resulted in a small increase in Bcl-xL expression while Id2 transcript levels and cell replication were unchanged in human islets. In contrast, overexpression of mouse Pax4 induced human islet cell proliferation. Treatment of islets with 5-Aza-2'-deoxycytidine induced Pax4 without stimulating Bcl-xL and Id2 expression. Human Pax4 DNA binding activity was found to be lower than that of the mouse homologue. Thus, human pax4 gene expression is epigenetically regulated and induced by physiological stimuli through the concerted action of multiple signalling pathways. However, it is unable to initiate the transcriptional replication program likely due to post-translational modifications of the protein. The latter highlights fundamental differences between human and rodent islet physiology and emphasizes the importance of validating results obtained with animal models in human tissues.
Keywords
Activins/pharmacology, Animals, Betacellulin, Cell Proliferation/drug effects, Diabetes Mellitus, Type 2/complications/genetics/metabolism, Epigenesis, Genetic, Gene Expression, Glucagon-Like Peptide 1/pharmacology, Glucose/pharmacology, Homeodomain Proteins/*genetics/*metabolism, Humans, In Vitro Techniques, Insulin/metabolism, Insulin Secretion, Insulin-Secreting Cells/cytology/drug effects/metabolism, Intercellular Signaling Peptides and Proteins/pharmacology, Interleukin-1beta/genetics, Islets of Langerhans/drug effects/*metabolism, Mitogens/pharmacology, Obesity/complications/genetics/metabolism, Paired Box Transcription Factors/*genetics/*metabolism, RNA, Messenger/genetics/metabolism, Rats, Signal Transduction, Transfection, fas Receptor/genetics
Pubmed
Create date
14/06/2021 8:58
Last modification date
18/09/2021 5:38
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