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J. Biol. Chem., Vol. 279, Issue 5, 3852-3861, January 30, 2004

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C/EBP- Induction by gp130 Signaling

ROLE IN TRANSITION TO MYELIN GENE EXPRESSING PHENOTYPE IN A MELANOMA CELL LINE MODEL^*

Anil K. Kamaraju, Sophie Adjalley, Peilin Zhang, Judith Chebath, and Michel Revel

From the Department of Molecular Genetics, Weizmann Institute of Science, Rehov Herzl, Rehovot 76100, Israel

Expression of genes encoding structural myelin proteins marks the inception of the myelinating Schwann cell (SC) phenotype. Earlier embryonic SC as well as adult non-myelinating SC produce the intermediate filament glial fibrillary acid protein (GFAP), which disappears from the myelinating SC. We previously observed that triggering of the gp130 receptor system by the IL6RIL6 ligand, comprising interleukin-6 (IL-6) fused to the soluble IL-6 receptor, induces myelin gene expression in rat embryonic dorsal root ganglia (DRG) cultures as well as in the murine melanoma cell line B16/F10.9. Study of target genes regulated by IL6RIL6 indicates a strong and selective induction of the transcriptional regulator C/EBP- in DRG cultures and in the F10.9 cell line. As shown here, silencing of C/EBP- mRNA and protein expression by introduction of small interference RNA-producing plasmids in the F10.9 cells prevented the induction of myelin protein zero (P0) and myelin basic protein (MBP) mRNAs by IL6RIL6. Doxycycline-regulated overexpression of C/EBP- was sufficient to induce accumulation of P0 and MBP mRNAs, the effect being selective, because C/EBP- did not affect several other genes strongly regulated by IL6RIL6. Interestingly, GFAP was inhibited by C/EBP- overexpression, leading to a modulation of the ratio between myelin gene products versus GFAP and suggesting that C/EBP- plays a role in the switch to a myelinating phenotype. The down-regulation of Pax3, also typical of the transition to myelinating cells, was observed after C/EBP- expression in correlation to P0 induction and to decrease of melanogenesis and cell growth. In cultures of dissociated cells of embryonic rat DRG, where we knocked-down the C/EBP- mRNA, we found an inhibition of P0 mRNA induction by IL6RIL6, showing that the role of C/EBP- on this myelin gene is not unique to the melanoma system.

Received for publication, September 22, 2003 , and in revised form, October 30, 2003.

^* This work was supported by InterPharm (Weizmann Industrial Park, Israel) and Serono Group (Geneva, Switzerland). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 972-8-934-2103 (or -2101); Fax: 972-8-9343174; E-mail: michel.revel{at}weizmann.ac.il.

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