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Volume 271, Number 42, Issue of October 18, 1996 pp. 25950-25957
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Okadaic Acid Suppresses Neural Differentiation-dependent Expression of the Neurofilament-L Gene in P19 Embryonal Carcinoma Cells by Post-transcriptional Modification

(Received for publication, April 16, 1996, and in revised form, June 24, 1996)

Yoji Sasahara ^§ , Takayasu Kobayashi , Hiroshi Onodera , Masatoshi Onoda , Motoko Ohnishi , Shunsuke Kato , Kazuyuki Kusuda , Hiroshi Shima ^¶ , Minako Nagao ^¶ , Hiroshi Abe , Yuchio Yanagawa , Akira Hiraga and Shinri Tamura

From the Departments of  Biochemistry and ^§ Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980, Japan, the ^¶ Carcinogenesis Division, National Cancer Center Research Institute, Tokyo 104, Japan, and the  Department of Morphology, Division of Human Structure and Function, Tokai University School of Medicine, Isehara 259-11, Japan

Mouse P19 embryonal carcinoma cells in aggregation culture in the presence of 10⁶ M retinoic acid followed by monolayer culture differentiate into nerve and glial cells. In this study, we demonstrated that the neurofilament-L (NF-L) mRNA and protein levels of these cells were enhanced in accordance with their retinoic acid-induced neural differentiation. Okadaic acid (OA) treatment of the cells markedly suppressed this differentiation-dependent NF-L gene expression increase and neurite outgrowth of the cells. Similar results were obtained when tautomycin was used instead of OA, suggesting that inhibition of protein phosphatase(s) is involved in the suppression of neural differentiation. OA treatment did not affect the NF-L gene transcription level, determined by the nuclear run-on transcription assay, but it did reduce the stability of both the 3.5- and 2.3-kilobase NF-L mRNAs. The expression and activity levels of protein phosphatase 2A (PP2A) and 2B (PP2B) but not protein phosphatase 1 (PP1) in P19 cells increased in accordance with the enhanced NF-L gene expression. The presence of OA in the culture medium during the course of the neural differentiation caused a reduced PP2A activity but not PP1 and PP2B activities of the cell extracts. On the other hand, both PP1 and PP2B activities but not PP2A activity of cell extracts were suppressed by the addition of cyclosporin A or FK506 in the culture medium. However, both cyclosporin A and FK506 treatments affected neither NF-L gene expression nor neurite outgrowth. These results demonstrate that the OA treatment inhibits the differentiation-dependent increase in NF-L gene expression by destabilizing its mRNAs and suggest that PP2A plays key roles in the differentiation-dependent enhanced expression of the NF-L gene and is the point of the action of OA.

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