Activation of myelin genes during transdifferentiation from melanoma to glial cell phenotype.
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.
Slutsky
Shalom G
SG
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Kamaraju
Anil K
AK
Levy
Alon M
AM
Chebath
Judith
J
Revel
Michel
M
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D051767:Early Growth Response Protein 2; D017930:Genes, Reporter; D005822:Genetic Vectors; D006609:High Mobility Group Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000235:genetics* / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055757:SOXE Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D006609:High Mobility Group Proteins; D015850:Interleukin-6; D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D012333:RNA, Messenger; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors; D004318:Doxycycline