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J. Biol. Chem., Vol. 278, Issue 11, 8960-8968, March 14, 2003
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From the Department of Molecular Genetics, Weizmann Institute of
Science, Rehovot 76100, Israel
Induction of myelin genes occurs around
birth in the last stage of Schwann cells differentiation and is
reactivated in case of nerve injury. Previous studies showed that
activation of the gp130 receptor system, using as ligand interleukin-6
fused to its soluble receptor (IL6RIL6), causes induction of myelin
genes such as myelin basic protein (MBP) and myelin protein zero (Po) in embryonic dorsal root ganglia Schwann cells. We also reported that
in murine melanoma B16/F10.9 cells, IL6RIL6 causes a shut-off of
melanogenesis mediated by a down-regulation of the paired-homeodomain factor Pax3. The present work demonstrates that these IL6RIL6-treated F10.9 cells undergo transdifferentiation to a myelinating glial phenotype characterized by induction of the transcriptional activities of both Po and MBP promoters and accumulation of myelin gene products. For both Po and MBP promoters, a repression by Pax3 and stimulation by
Sox10 can be demonstrated. Because after IL6RIL6-treatment, Pax3
disappears from the F10.9 cells (as it does in mature myelinating Schwann cells) whereas the level of Sox10 rather increases, we modulated the relative level of these factors and show their
involvement in the induction of myelin gene expression by IL6RIL6.
In addition, however, we show that a C/G-rich CACC box in the Po
promoter is required for activation by IL6RIL6, as well as by ectopic
Sox10, and identify a Kruppel-type zinc finger factor acting through this CACC box, which stimulates Po promoter activity.
Activation of Myelin Genes during Transdifferentiation from
Melanoma to Glial Cell Phenotype*
*
This work was supported by Interpharm (Weizmann Industrial
Park, Israel) and Ares Serono Group (Geneva, Switzerland).The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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.:
972-8-9342101; Fax: 972-8-9344108; E-mail:
michel.revel@weizmann.ac.il.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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