title: Sox6 suppression induces RA-dependent apoptosis mediated by BMP-4 expression during neuronal differentiation in P19 cells.
abstract: Sox6 is a transcription factor that induces neuronal differentiation in P19 cells; its suppression not only inhibits neuronal differentiation but also induces retinoic acid (RA)-dependent apoptosis of P19 cells. In the present study, we found that Sox6 suppression-induced apoptosis was mediated by activation of caspase 9 and 3. Moreover, we noted a weak leakage of cytochrome c into the cytoplasm from the mitochondria, indicating that apoptosis occurs through a mitochondrial pathway in Sox6-suppressed P19 (P19[anti-Sox6]) cells. Sox6 suppression in the presence of RA also induced the expression and secretion of bone morphogenetic protein 4 (BMP-4). Addition of an anti-BMP-4 antibody for neutralization increased cell viability and led to RA-dependent death of P19[anti-Sox6] cells. Our results indicate that Sox6 suppression induces RA-dependent cell death of P19 cells, mediated by BMP-4 expression and secretion. Normally, high Sox6 expression leads to RA-mediated neuronal differentiation in P19 cells; however, Sox6 deficiency induces production and secretion of BMP-4, which mediates selective cell death. Our findings suggest that Sox6 contributes to cell survival by suppressing BMP-4 transcription during neuronal differentiation.
authors.affiliation: Division of Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Minatojima, Chuo-Ku, Kobe, 650-8586, Japan. hamada@pharm.kobegakuin.ac.jp.
authors.forename: Michiko
authors.initials: M
authors.lastname: Hamada-Kanazawa
authors.affiliation: Division of Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Minatojima, Chuo-Ku, Kobe, 650-8586, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.affiliation: Division of Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Minatojima, Chuo-Ku, Kobe, 650-8586, Japan.
authors.forename: Masaoki
authors.initials: M
authors.lastname: Takano
authors.affiliation: Division of Biopharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Minatojima, Chuo-Ku, Kobe, 650-8586, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Miyake
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004789:Enzyme Activation; D051379:Mice; D055755:SOXD Transcription Factors / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D014212:Tretinoin; D020169:Caspases
keywords: Apoptosis; BMP-4; BMPRIB; P19; Retinoic acid; Sox6