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.