p38 MAPK is involved in activin A- and hepatocyte growth factor-mediated expression of pro-endocrine gene neurogenin 3 in AR42J-B13 cells.
Neurogenin3 (ngn3) is a transcription factor that is essential for the differentiation of pancreatic endocrine cells. To investigate the signaling pathway that regulates ngn3 expression, we used AR42J-B13 cells as a model of the differentiation of pancreatic islets. In these cells, treatment with activin A and hepatocyte growth factor (HGF) induced the expression of ngn3. Reporter gene analysis using human ngn3 gene (NEUROG3) promoter fragments of various lengths identified the region between -402 and -327 bp of NEUROG3 as an activin A- and HGF-responsive DNA sequence. This DNA sequence normally functions as a repressor in AR42J-B13 cells, but treatment with activin A and HGF negates the repressor activity. Interestingly, function of the activin A- and HGF-responsive sequence was not influenced by the overexpression of the Smad inhibitory factor, Smad7. Instead, activin A and HGF activation was inhibited by overexpression of a dominant-negative mutant of transforming growth factor-beta-activated kinase 1 (TAK1), or mitogen-activated protein kinase kinase 3 (MKK3), or by treatment with a p38 MAPK-specific inhibitor, SB203580. Activin A and HGF function through the TAK1-MKK3-p38 MAPK pathway to relieve transcription repressors located between -402 and -326 bp on the NEUROG3 promoter, and consequently activate ngn3 expression and endocrine differentiation of AR42J-B13 cells.
Ogihara
Takeshi
T
Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Watada
Hirotaka
H
Kanno
Rei
R
Ikeda
Fuki
F
Nomiyama
Takashi
T
Tanaka
Yasushi
Y
Nakao
Atsuhito
A
German
Michael S
MS
Kojima
Itaru
I
Kawamori
Ryuzo
R
D028341:Activins / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004702:Endocrine Glands / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D017930:Genes, Reporter; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D028341:Activins; D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004791:Enzyme Inhibitors; D017228:Hepatocyte Growth Factor; D028322:Inhibin-beta Subunits; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C498695:NEUROG3 protein, human; C422405:activin A