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p38 MAP kinase interacts with and stabilizes pancreatic and duodenal homeobox-1.

Abstract：

:Pancreatic and duodenal homeobox-1 (PDX-1) is a homeodomain-containing transcription factor that plays a critical role in pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis. PDX-1 is subjected to extensive post-translational modifications for its stability, subcellular location and transactivity. We report here that PDX-1 expression is up-regulated by p38 MAP kinase. Antibody array screen identified p38 as a candidate PDX-1-interacting protein in GFP-PDX-1 stable HEK293 cells. The p38-PDX-1 interaction was confirmed by immunoprecipitation/Western blotting analysis in both transient transfection system of HEK293 cells and endogenous system of β-TC-6 cells stimulated by glucagon-like peptide 1 (GLP-1). Co-transfection of p38 with PDX-1 resulted in increased PDX-1 expression in HEK293 cells, which was accompanied by a decreased PDX-1 ubiquitination. Mass spectrometry analysis showed that Ser 268 of human PDX-1 was phosphorylated in GFP-PDX-1 stable HEK293 cells. Functional mutagenesis analysis showed that mutation of Ser 269 of mouse PDX-1 (corresponding to Ser 268 of human PDX-1) into nonphosphorylatable alanine abolished the stabilizing effect of p38 on PDX-1, which was in line with enhanced PDX-1 ubiquitination and shortened half-life of PDX-1. p38 showed kinase activity towards PDX-1 in vitro, suggesting that Ser 269 is a potential p38-regulated phosphorylation site within PDX-1. GLP-1-stimulated PDX-1 expression was accompanied by p38 kinase activation in mouse insulinoma β-TC-6 cells and p38 inhibitor SB202190 inhibited GLP-1-stimulated PDX-1 expression with accompanied inhibition of p38 kinase activation. Taken together, our studies indicated that p38 MAP kinase is a positive regulator of PDX-1 stability and that p38 exerts its stabilizing effect on PDX-1 through a phosphorylation-dependent inhibition of PDX-1 ubiquitination.

journal_name

Curr Mol Med

journal_title

Current molecular medicine

authors

Zhou G,Wang H,Liu SH,Shahi KM,Lin X,Wu J,Feng XH,Qin J,Tan TH,Brunicardi FC

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

377-86

issue

eissn

1566-5240

issn

1875-5666

pii

CMM-EPUB-20130115-7

journal_volume

pub_type

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p38 MAP kinase interacts with and stabilizes pancreatic and duodenal homeobox-1.