Implication of Trip15/CSN2 in early stage of neuronal differentiation of P19 embryonal carcinoma cells.
Trip15/CSN2 is a transcriptional corepressor/a component of COP9 signalosome (CSN) and participates in various signaling pathways. However, participation of Trip15/CSN2 in neural differentiation is still obscure. Here, we show that Trip15/CSN2 plays a critical role in neuronal differentiation. The expression of Trip15/CSN2 mRNA was induced at an early stage of neuronal differentiation in the retinoic acid (RA)-treated P19 cells, but not in the triiodothyronine (T3)-primed cardiac muscular cell differentiation. The expression of Trip15/CSN2 mRNA in the rat brain was detected at E14 and the protein was localized in the nuclei of neonatal rat CNS neurons. Enforced expression of sense rat Trip15/CSN2 mRNA caused the downregulation of Oct-3/4 mRNA expression and was sufficient to convert P19 cells into neurons, but not glial cells, only after the aggregation without RA. In the presence of RA, exogenous expression of the sense mRNA caused the intense and rapid induction of neurogenic Brn-2 and Mash-1 mRNA expressions accompanying the strong downregulation of Oct-3/4 mRNA expression, and stimulated both neuronal and glial cell differentiations of P19 cells. In contrast, enforced expression of the antisense mRNA suppressed the commitment of RA-treated aggregation form of P19 cells to neuronal lineage. These data strongly suggest that Trip15/CSN2 could implicate in the commitment of multipotent embryonal carcinoma (EC) cells to neuronal fate through the downregulation of Oct-3/4 which suppresses neurogenic genes. Moreover, in addition to Trip15/CSN2, RA-regulated other factor(s) may be required for glial cell differentiation.
Akiyama
Hirotada
H
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Yamazaki, Noda-shi, Chiba 278-8510, Japan.
Sugiyama
Akinori
A
Uzawa
Kouji
K
Fujisawa
Naoko
N
Tashiro
Yousuke
Y
Tashiro
Fumio
F
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D000075686:COP9 Signalosome Complex; D018236:Carcinoma, Embryonal / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology*; D003001:Cloning, Molecular; D017931:DNA Primers; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C118919:Cops2 protein, mouse; D017931:DNA Primers; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D000075686:COP9 Signalosome Complex