title: Inhibition of Src and p38 MAP kinases suppresses the change of claudin expression induced on dedifferentiation of primary cultured parotid acinar cells.
abstract: Sjögren's syndrome and therapeutic radiation for head and neck cancers result in irreversible changes in the parenchyma of salivary glands, loss of acinar cells, prominence of duct cells, and fibrosis. To clarify mechanisms of salivary gland dysfunction, we identified a signaling pathway involved in the dedifferentiation of primary cultures of parotid acinar cells. We reported previously that the expression pattern of claudins changes during culture, is related to the three-dimensional organization of the cells, and reflects their ability to function as acinar cells. In this study, we found that this change of claudin expression is a process of dedifferentiation, because expression of other differentiation markers also changes during culture. The expression levels of claudins-4 and -6, cytokeratin 14, and vimentin are increased, and those of claudin-10, aquaporin 5, and amylase are decreased. Inhibitors of Src and p38 MAP kinases suppress these changes and increase the expression of acinar marker proteins. Differences in extracellular matrix components have no effect. Activation of p38 MAP kinase occurs during cell isolation from the parotid glands and is retained up to 6 h after the isolation. In contrast, activation of Src kinases does not increase during the cell isolation. The Src inhibitor PP1 suppresses the activation of p38 MAP kinase. Therefore, cellular stresses induced during cell isolation cause dedifferentiation and transition to duct-like cells through activation of p38 MAP kinase and constitutively active Src kinases.
authors.affiliation: Dept. of Physiology, Nihon Univ. School of Dentistry at Matsudo, Sakaecho-nishi 2-870-1, Matsudo, Chiba 271-8587, Japan. yoshigaki.junko@nihon-u.ac.jp
authors.forename: Junko
authors.initials: J
authors.lastname: Fujita-Yoshigaki
authors.forename: Miwako
authors.initials: M
authors.lastname: Matsuki-Fukushima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiya
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D051402:Aquaporin 5 / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D062506:Claudin-4; D057167:Claudins; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D053547:Keratin-14 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010306:Parotid Gland / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014746:Vimentin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C509621:4-amino-7-phenylpyrazol(3,4-d)pyrimidine; C412373:AG 1879; D000873:Anthracenes; C496040:Aqp5 protein, rat; D051402:Aquaporin 5; D002070:Butadienes; D062506:Claudin-4; D057167:Claudins; D007093:Imidazoles; D053547:Keratin-14; D008565:Membrane Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C113580:U 0126; D014746:Vimentin; C502009:claudin 10; C432165:pyrazolanthrone; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000681:Amylases; C122101:claudin 6; C093642:SB 203580