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. 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. Axonal myelination is a function of specialized glial cells, oligodendrocytes in the brain and myelinating Schwann cells (SC) 1The abbreviations used are: SC, Schwann cell(s); MBP, myelin basic protein; Po, protein zero; IL, interleukin; IL6R, IL-6 receptor; IL6RIL6, IL-6 fused to its soluble receptor; DRG, dorsal root ganglia; MITF, microphtalmia-associated transcription factor; RT, reverse transcription; F, forward; R, reverse; G3′PDH, glyceraldehyde 3′-phosphodehydrogenase; nt, nucleotides; 3-AT, 3-amino-1,2,4-triazole; TK, thymidine kinase in peripheral nerves, whose impairment in demyelinating diseases affects nerve function and integrity. Maturation of cells producing myelin occurs around birth and needs to be reactivated for repair of nerve injury (1Stoll G. Muller H.W. Brain Pathol. 1999; 9: 313-325Google Scholar). The developmental stages from neural crest-derived precursors to mature myelinating SC were defined by specific gene markers (see Refs.2Jessen K.R. Mirsky R. Glia. 1991; 4: 185-194Google Scholar, 3Jessen K.R. Mirsky R. Microsc. Res. Tech. 1998; 41: 393-402Google Scholar, 4Zorick T.S. Lemke G. Curr. Opin. Cell Biol. 1996; 8: 870-876Google Scholar, 5Kioussi C. Gruss P. Trends Genet. 1996; 12: 84-86Google Scholar for reviews). At early stages, embryonic SC express low affinity nerve growth factor receptor, neural cell adhesion molecule (N-CAM), glial fibrillary acidic protein (GFAP), the transcription factors paired homeodomain Pax3, and later POU domain Octamer-6 (Oct-6)/suppressed cAMP-inducible POU (SCIP). This phenotype also characterizes the adult non-myelinating SC and reappears after nerve injury. Maturation of myelinating SC is marked by disappearance of these early markers, including Pax3, and the induction of myelin genes such as myelin basic protein (MBP) and protein zero (Po or myelin protein zero). Promoters driving glial-specific expression of Po (6Lemke G. Lamar E. Patterson J. Neuron. 1988; 1: 73-83Google Scholar, 7Messing A. Behringer R.R. Hammang J.P. Palmiter R.D. Brinster R.L. Lemke G. Neuron. 1992; 8: 507-520Google Scholar, 8Brown A.M. Lemke G. J. Biol. Chem. 1997; 272: 28939-28947Google Scholar) and of MBP (9Miura M. Tamura T. Aoyama A. Mikoshiba K. Gene. 1989; 75: 31-38Google Scholar, 10Foran D.R. Peterson A.C. J. Neurosci. 1992; 12: 4890-4897Google Scholar, 11Gow A. Friedrich Jr., V.L. Lazzarini R.A. J. Cell Biol. 1992; 119: 605-816Google Scholar, 12Goujet-Zalc C. Babinet C. Monge M. Timsit S. Cabon F. Gansmuller A. Miura M. Sanchez M. Pournin S. Mikoshiba K. et al.Eur. J. Neurosci. 1993; 5: 624-632Google Scholar, 13Wrabetz L. Shumas S. Grinspan J. Feltri M.L. Bozyczko D. McMorris F.A. Pleasure D. Kamholz J. J. Neurosci. Res. 1993; 36: 455-471Google Scholar, 14Forghani R. Garofalo L. Foran D.R. Farhadi H.F. Lepage P. Hudson T.J. Tretjakoff I. Valera P. Peterson A. J. Neurosci. 2001; 21: 3780-3787Google Scholar) were identified transcription factors (see M. Glia. Scholar for the domain Sox10, present in early neural cells, the Po promoter D. M. Biol. Scholar). a of myelinating SC differentiation required for myelination P. S. G. A. T. Babinet C. P. stimulates expression of myelin genes T.S. A. T. Lemke G. 1999; Scholar, R. J. T. M. J. Neuron. 2001; Scholar). Pax3 expression of MBP C. Gruss P. Neuron. and does R. Lemke G. 1993; in the for of Pax3 and to the differentiation of myelinating factors acting SC, a be to myelin gene The SC growth factor growth factor A. G. Mirsky R. K.R. Neuron. early SC differentiation stages the induction of MBP and Po genes L. Neuron. 1996; Scholar). growth factor or growth Po gene expression L. K.R. Mirsky R. Scholar). Axonal to for myelin gene expression in SC G. M. 1988; Scholar) and in P. Lemke G. J. Neurosci. 1988; 8: Scholar). The these well by Po and MBP G. M. 1988; Scholar, L. K.R. Mirsky R. J. Cell Biol. 1991; Scholar) whereas it Pax3 C. Gruss P. Neuron. Scholar). of were the promoters of the genes myelin Po (6Lemke G. Lamar E. Patterson J. Neuron. 1988; 1: 73-83Google MBP R. J. 1993; Scholar, L. Kamholz J. J. and peripheral myelin D. E. M. Gene. Scholar). such as and also Po and promoter activities F. A.M. Lemke G. M. J. 1998; Scholar, F. S. M. Brain Res. Scholar). of factors IL-6 that the gp130 receptor a of this (see T. T. 1997; Scholar for we used a protein IL6RIL6 from the of IL-6 to its soluble IL-6 receptor that the gp130 in cell and a affinity for gp130 J. D. A. T. M. S. A. S. M. 1997; 8: Scholar, R. J. A. L. M. T. 1999; Scholar). We showed that this gp130 stimulates the expression of MBP and Po and in of embryonic dorsal root ganglia as well as in SC S. J. M. 1999; Scholar, S. G. A. J. M. J. Neurosci. Res. 2001; Scholar). IL6RIL6 the expression of Pax3 in these embryonic cells. IL6RIL6 the of in nerve S. G. A. J. M. J. Neurosci. Res. 2001; Scholar). that IL6RIL6 MBP in brain cells, as The of these is by the that in the of gp130 after birth causes of myelin and SC in peripheral M. K. T. T. K. K. Muller J. 1998; Scholar). We show in which the gp130 IL6RIL6 the expression of myelin genes and causes transdifferentiation of melanoma cells a glial The murine melanoma B16/F10.9 cells undergo growth to the of IL-6 its soluble IL-6 receptor A. S. L. M. J. 1997; Scholar) or to the IL6RIL6 J. D. A. T. M. S. A. S. M. 1997; 8: Scholar). is a of the of a in Pax3, which the microphtalmia-associated transcription factor gene in the C. J. M. J. Biol. Chem. Scholar). The present work demonstrates that IL6RIL6 expression of the myelin Po and MBP through transcriptional This melanoma a to the transcription factors in the of myelin genes expression and their induction by IL-6 melanoma F10.9 cells A. A. M. M. L. J. 1993; Scholar, A. M. L. J. 1989; Scholar) were as a in and were IL6RIL6 as J. D. A. T. M. S. A. S. M. 1997; 8: Scholar, R. J. A. L. M. T. 1999; Scholar) using cells and of the protein as by the For were in the of in and of the used for The used to specific were as Pax3 and reverse Sox10 and glial fibrillary acidic protein and Po from and and MBP and were used to were for or for The of for Pax3 and Sox10 in a as by the were a MBP and by the and and were as C. J. M. J. Biol. Chem. Scholar). kinase were used as of R. F10.9 used as C. J. M. J. Biol. Chem. Scholar) to the of and Sox10 The were in the expression The of P. and P. of the protein in of and in of the gene We of F10.9 cells Sox10 or Pax3 gene expression can be of to the growth We F10.9 cell the reverse from the in using as C. J. M. J. Biol. Chem. Scholar). The were for growth and to IL6RIL6 by In the cells, we the a In the to the we the for the protein or Sox10 or Pax3 the cell in the of and after were of the ectopic by using the reverse and Sox10 or Pax3 The MBP (9Miura M. Tamura T. Aoyama A. Mikoshiba K. Gene. 1989; 75: 31-38Google Scholar) of C. and and to the MBP gene The in of the in the basic by and to the The and the MBP and by to or and to The Po promoter (6Lemke G. Lamar E. Patterson J. Neuron. 1988; 1: 73-83Google Scholar) by using the F, and R, the relative to the of in basic to For Po gene by as and F, and R, The in basic The were For of the Po the used as for F, and R, or The or of the Po were the and were in of the promoter in the by by using as a the of in of the gene in We by a of this by using F, in and in of the from The reverse the of the The by in basic by by using in of the in its were used to the in a for the were to the were for and for and for and for The and by The by and to the The and cells. For F10.9 cells were in well of a a of of of of the Po or MBP of and or Sox10 or Pax3 expression of in for of and the were IL6RIL6, and were for the used to activities to the were from were from F10.9 cells in for in the or of IL6RIL6 The cell a in of by were and in were and in by and for The by a in to cell of by for and for The were and the last and a of in A. is the as of Po promoter (see were and the a of the of for in a of The and and of and For of or CACC were used as or The from used to the the CACC box of the myelin Po promoter were in of the and were after these and for growth in and of from from F10.9 melanoma cells that for IL6RIL6. The and were used for in the to the activation domain the in the and and were from the by E. were in the in the and for that as in the of as in the of 3-AT, were and from and of the were for from F10.9 cells or IL6RIL6 were in expression and used for as reported C. J. M. J. Biol. Chem. of the melanoma F10.9 cells by the gp130 IL6RIL6 a in from cells to cells that to cell to the cell the IL6RIL6-treated cells in the and the We C. J. M. J. Biol. Chem. Scholar) that the of IL6RIL6 from the in the transcription factor MITF, that is of the of Pax3 from the cells. that the Pax3 a induction of MBP in the IL6RIL6-treated melanoma cells. accumulation of MBP from to for myelin Po, which is the in the peripheral nerve myelin by Schwann cells, were by IL6RIL6 in the F10.9 cells from The of myelin T.J. McMorris F.A. J. Res. by IL6RIL6 in the F10.9 melanoma cells also induction of and of The F10.9 melanoma cell to IL6RIL6 can be defined as a the cells from a which is the cells by C. J. M. J. Biol. Chem. to a phenotype of myelinating Schwann expression of Pax3 Po and MBP promoter down-regulation of Pax3 IL6RIL6 for promoter F10.9 cells MBP promoter and of to as is IL6RIL6 or Po promoter in the of the by IL6RIL6 and its repression by of the in of Po or MBP of from F10.9 or IL6RIL6 Sox10 and after for Sox10 in F10.9 cells and IL6RIL6 for the induction of the MBP and Po IL6RIL6 from transcriptional gene we the of the murine MBP promoter (9Miura M. Tamura T. Aoyama A. Mikoshiba K. Gene. 1989; 75: 31-38Google Scholar) in of the This of the promoter expression in cell and in myelinating oligodendrocytes in L. C. Feltri M.L. A. R. A. Kamholz J. J. 1998; Scholar). of the F10.9 cells this gene that the MBP gene a transcriptional activation of in to the IL6RIL6 For the myelin Po the to of the which specific expression in Schwann cells (6Lemke G. Lamar E. Patterson J. Neuron. 1988; 1: 73-83Google Scholar, 7Messing A. Behringer R.R. Hammang J.P. Palmiter R.D. Brinster R.L. Lemke G. Neuron. 1992; 8: 507-520Google were in the gene and F10.9 cells. IL6RIL6 the of this myelin Po promoter Because of the of IL6RIL6 in the F10.9 cells is the of Pax3 protein C. J. M. J. Biol. Chem. we Pax3 be in the of the myelin Po gene promoter as reported for the MBP gene in Schwann cells C. Gruss P. Neuron. Scholar). The F10.9 cells were a Pax3 expression in to the MBP and Po promoter The induction of the promoter activities for both MBP and Po expression of Pax3. of Pax3 in the of IL6RIL6 the myelin Po and MBP gene promoters the of Pax3 the MBP gene is in the melanoma F10.9 cells and can be to the peripheral myelin Po as to by Pax3 the Po promoter and a also be a Po promoter of the Po promoter does the of Pax3 the that Pax3 In this repression the myelin Po and the MBP promoters that the down-regulation of Pax3 by IL6RIL6 to the induction of the myelin gene The B16/F10.9 cells express Sox10, factor to be in both E. M. M. Genet. 9: Scholar, M. Genet. Scholar, C. K. J.P. R. J. Biol. Chem. Scholar, M. J. C. R. J. Biol. Chem. Scholar) and SC differentiation M. Glia. Scholar, D. M. Biol. K. E. I. M. J. Neurosci. 1998; Scholar). in Sox10 by after IL6RIL6 to the cells This induction by which in Sox10 of and and The of Sox10 protein by in of F10.9 cells showed also which the in Pax3 protein We reported C. J. M. J. Biol. Chem. Scholar) that this in Sox10 is the after IL6RIL6 Sox10 in and to a in the level of Sox10 protein in the cell Sox10 expression showed that Sox10 is in the activation of the MBP promoter in the F10.9 melanoma cells IL6RIL6 In the the Pax3 the MBP Induction by Sox10 the MBP including the the of the MBP promoter however, to to Sox10 or IL6RIL6 show that MBP transcription in F10.9 cells is Sox10, as S. M. P. D. M. M. Scholar) in oligodendrocytes and in of Sox10 the F10.9 melanoma the Po promoter transcriptional activation in a in the of IL6RIL6 At of Sox10 the Po the activation to that by IL6RIL6. of Sox10 In the cells by IL6RIL6, Sox10 the Po promoter and the MBP promoter in these cells, Sox10 to be a factor in the of the MBP and Po the cells by the gp130 the of Pax3 and Sox10 the induction of Po the F10.9 cells were Pax3 and Sox10 the of a The of Pax3 and Sox10 were by in the cells by or IL6RIL6 or both and in we the of myelin Po In cells that Pax3 the level of Po by IL6RIL6 by as the level in the of The level of Po also low in the Pax3 a protein the Po induction or as the in that the induction of the Po by IL6RIL6 is Pax3 is in the IL6RIL6-treated cells, in the that the down-regulation of Pax3 by the gp130 for a of the accumulation of the myelin gene a that ectopic Sox10 in to we of Po the in Sox10 by that in IL6RIL6-treated cells the in Po the by IL6RIL6 the in Sox10 by IL6RIL6 for of the induction of the Po by IL6RIL6 This we the Po promoter required for the transcriptional activation by IL6RIL6. The Po promoter expression of Po a of for transcription factors A.M. Lemke G. J. Biol. Chem. 1997; 272: 28939-28947Google Scholar, D. M. Biol. of which in A. Po promoter from or to activation by IL6RIL6 from to in a of induction by IL6RIL6, of the and from to the of the promoter of the of the and were and of a in a the Po to by IL6RIL6, its the The of the Po promoter the Sox10 and as characterized by et D. M. Biol. Sox10 and the Po promoter activation in cells to express Sox10 by We the of these as of a of in the to in of the Sox10 by a in the of the promoter and the induction of the Sox10 and also the induction by IL6RIL6, the both were we that the Sox10 and also the of the Po promoter and its by IL6RIL6. In the C/G-rich or CACC box of the and to IL6RIL6 in the Po Po and Po The and around a Sox10 that the induction by IL6RIL6 is of of myelin gene Po promoter as of IL6RIL6. The for and and of induction after the and basic Po Po Po in the Po promoter in Sox10 in the Po promoter in Sox10 Sox10 Sox10 as of IL6RIL6. The for and and of induction after the and basic in the Po promoter in D. in a The induction of Po promoter by ectopic Sox10 as by of the Sox10 and or of the CACC box the induction by ectopic Sox10 as it for the IL6RIL6 the of this also the of the Po promoter in to IL6RIL6 and Sox10 as a of which the C/G-rich a in which Sox10 or factor to the CACC box its C/G-rich a of and and which were by the that the the CACC box the to or also the of these the were of cells, IL6RIL6 a in the of a in a in In of a factor that through this of the Po we used a in from IL6RIL6-treated F10.9 cells for a protein that a the of the Po of by of growth (see and identified a a This by to the of a and that its of the F10.9 cells by IL6RIL6 M. Res. 1999; Scholar) as a of a of transcription factors that a of Kruppel-type zinc and to CACC such as that in the gene promoter whose and that of the in the Po promoter (see as of transcription M. Res. 1999; we that it stimulates the myelin Po promoter in the F10.9 melanoma cells, the by the transcriptional of the whereas a of The of Sox10 a stimulation of the Po the of factor and to that IL6RIL6 of the cells The its or Sox10 or IL6RIL6. of the CACC box in the Po promoter as the of the of this CACC box for as for the In addition, the of also the Sox10 and in the Po promoter were a the CACC box factor and Sox10 in the activation of the Po promoter In to which is in the of the Po promoter and after IL6RIL6 to to the and to the that present in and in which after IL6RIL6. Because to be required for myelination in SC P. S. G. A. T. Babinet C. P. Scholar) and to C/G-rich P. C. M. P. D. P. J. 9: we it be of the acting the through the C/G-rich of this CACC expression of in the F10.9 cells the promoter by a marked both and Sox10 were in the melanoma cells The of Sox10 for the to Sox10 and were the the stimulation by as well as the the of Sox10 the of be of the the of of Sox10 or IL6RIL6 C/G-rich also the to the work through The showed that the of IL6RIL6 Po promoter the of the to We also that IL6RIL6 the level of present in these F10.9 cells the CACC box to be the in to its Sox10 for the activation of the Po promoter by IL6RIL6, as well as by Sox10 in the F10.9 melanoma of or Sox10 the Po to in to in D. in a the Po promoter to IL6RIL6, Sox10, and of For or induction of in of the Po in IL6RIL6-treated cells or IL6RIL6 Sox10 or Po of For or induction of in of the Po in IL6RIL6-treated cells or IL6RIL6 Sox10 or in a The gp130 IL6RIL6 myelin gene expression in embryonic Schwann cells S. J. M. 1999; Scholar, S. G. A. J. M. J. Neurosci. Res. 2001; Scholar). We show that IL6RIL6 expression of the myelin genes in the murine B16/F10.9 melanoma cells. cells undergo a of their phenotype characterized by and expression C. J. M. J. Biol. Chem. Scholar) and of a myelinating Schwann cell and cells can such in J. Pathol. 1999; Scholar, C. R. A. Scholar). The transdifferentiation of the F10.9 cells that neural crest-derived or glial E. C. Curr. Opin. Genet. 4: Scholar, E. C. P. S. A. Scholar) and identify We in the transcriptional activation of promoters from myelin Po and of the that to both and myelin gene promoters is a down-regulation of Pax3 IL6RIL6 The Pax3 after IL6RIL6, by a in the protein C. J. M. J. Biol. Chem. Scholar). of this be of Pax3 its from to after IL6RIL6 Pax3 is of the gene A. K. M. Genet. 1998; and we that the of Pax3 by IL6RIL6 is for the of the its can be by ectopic expression of Pax3 C. J. M. J. Biol. Chem. Scholar). expression of Pax3 in the F10.9 cells the of IL6RIL6 to the promoters of the myelin Po and MBP of MBP gene induction by Pax3 in SC and in C. Gruss P. Neuron. Scholar). This is the of a repression of the Po gene is of that the down-regulation of Pax3 by the gp130 IL6RIL6 is also in of embryonic and SC, in which Po and MBP gene S. G. A. J. M. J. Neurosci. Res. 2001; Scholar). Because the in Pax3 is a of differentiation of myelinating SC C. Gruss P. Trends Genet. 1996; 12: 84-86Google this be by which gp130 myelin gene Pax3 in Sox10 to the and in of these genes of E. M. M. Genet. 9: Scholar, M. Genet. Scholar, C. K. J.P. R. J. Biol. Chem. Scholar, M. J. C. R. J. Biol. Chem. Scholar). the in Pax3 by IL6RIL6 in F10.9 cells, the Sox10 protein is rather after IL6RIL6 for that IL6RIL6, which differentiation of the cells, causes in Sox10, a factor for melanogenesis E. M. M. Genet. 9: Scholar, M. Genet. Scholar, C. K. J.P. R. J. Biol. Chem. Scholar, M. J. C. R. J. Biol. Chem. Scholar). we in IL6RIL6-treated F10.9 cells, Sox10 does and does Pax3 as it does in the F10.9 cells C. J. M. J. Biol. Chem. Scholar). This that the of Pax3 relative to Sox10, and the of their Sox10 from and also Sox10, it for acting The repression by Pax3 the Po promoter occurs Pax3 and be of Pax3 and factors as acting the myelin gene the of Sox10 in F10.9 cells by expression to induction of Po this induction that by IL6RIL6. This is of that Sox10 does work in the of myelin gene in embryonic SC Sox10 is present myelin gene to be K. E. I. M. J. Neurosci. 1998; Scholar) that Sox10 the transcriptional of the Po and MBP promoters in the F10.9 melanoma cells, as it does in cells D. M. Biol. Scholar, S. M. P. D. M. M. Sox10 to MBP promoters in cells M. M. Genet. 2001; Scholar). This that cells a for Sox10 or In of the to and to factors to transcription M. Trends Genet. Scholar). of Sox10, Pax3, for K. E. I. M. J. Neurosci. 1998; Scholar) and Scholar). Pax3, is that is SC myelin gene expression C. Gruss P. Trends Genet. 1996; 12: 84-86Google Scholar). For a in the Po promoter reported as required for the Po promoter A.M. Lemke G. J. Biol. Chem. 1997; 272: 28939-28947Google this is in the that we for the to IL6RIL6. in the of the Po promoter for that in the to IL6RIL6 and to that activation by IL6RIL6 and by Sox10 the Sox10 and defined by D. M. Biol. Scholar) in transcriptional around these such is a CACC box, which is defined by the the Po promoter to IL6RIL6, as well as to a this CACC box and of the IL6RIL6 whereas We identified a protein that this CACC box used as transcriptional in a system, as transcription factor The for is in the F10.9 cells IL6RIL6. as a CACC box from the gene promoter and to to a of defined by of Kruppel-type zinc M. Res. 1999; Scholar). reported to transcription of the gene to its factor M. Res. 1999; Scholar, D.R. J. Biol. Chem. 1998; Scholar). also to transcription of the gene through in cells M. Res. 1999; Scholar). of the F10.9 cells the of the Po and its a Po promoter in which Sox10 and were that a acting through the CACC box, stimulates Po promoter and a of Sox10 the CACC box The expression of the Kruppel-type factor that is in the IL6RIL6-treated melanoma cells be of the the Po promoter in these cells. transcription factors and to be in the function of the CACC box and its the Sox10 In to Pax3, Sox10 and we the of in the activation of the Po gene in F10.9 melanoma cells. is required for the of myelination SC P. S. G. A. T. Babinet C. P. and it a of SC genes including protein zero R. J. T. M. J. Neuron. 2001; Scholar). of the Po promoter by in SC T.S. A. T. Lemke G. 1999; Scholar) in D. M. Biol. and of and Sox10 reported the promoter A. K. M. Genet. 1998; Scholar). In the F10.9 cell system, expression the Po promoter and a The of to the CACC box, we identified that its the Po The F10.9 cells and IL6RIL6 its of In embryonic cell from of we L. J. and M. in that IL6RIL6 causes a in and in the induction of MBP and Po is for a of the IL-6 in the of In the of the IL-6 gp130 receptor in to nerve myelination M. K. T. T. K. K. Muller J. 1998; Scholar). the gp130 IL6RIL6, we stimulation of myelination in S. G. A. J. M. J. Neurosci. Res. 2001; Scholar) and in activation of myelin gene expression in Schwann cells from embryonic S. J. M. 1999; Scholar, S. G. A. J. M. J. Neurosci. Res. 2001; Scholar). The present melanoma cell a to the that myelin gene transcription in to the The of and is We for and the We P. and P. for the of expression and We C. and P. Gruss for the MBP gene