Sox10 acts as a tissue-specific transcription factor enhancing activation of the myelin basic protein gene promoter by p27Kip1 and Sp1.
Myelin basic protein (MBP) is one of the major components of the myelin sheath that insulates axons. In the central nervous system, MBP is synthesized by differentiating oligodendrocytes. The expression of MBP in oligodendrocytes is regulated mainly at the transcriptional level. The Sp1 family of transcription factors has been shown to be important in the regulation of many genes. Binding of Sp1 to the GC box in the proximal MBP promoter has been shown to be indispensable for the activation of MBP gene expression. Previous results from our laboratory have shown that the increase in p27Kip1 that accompanies oligodendrocyte differentiation is paralleled by an increase in Sp1. We also have shown that the increase in MBP expression resulting from elevated p27Kip1 levels is mediated through Sp1 and that this effect occurs specifically in oligodendrocytes. In this study, we found that increased expression of p27Kip1 together with the nervous-system-specific transcription factor Sox10 can activate the MBP promoter even in nonoligodendrocyte cells. This indicates that Sox10 confers cell type specificity on the expression of MBP. Both Sp1 and Sox10 can enhance MBP promoter activity when expressed alone. Cotransfection of plasmids encoding Sp1 and Sox10 induces increased activation of the MBP promoter over expression of either transcription factor alone. This effect is not limited to oligodendrocyte cell lines, in that Sp1 and Sox10 can also synergistically activate the MBP promoter when expressed in NIH3T3 fibroblasts. Mutation of the Sp1 binding sites in the MBP promoter eliminates Sox10 stimulated activation, suggesting that the MBP promoter is activated, at least in part, through protein-protein interactions between Sp1 and Sox10.
Wei
Qiou
Q
Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, South Dakota 57069, USA.
Miskimins
W Keith
WK
Miskimins
Robin
R
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D004676:Myelin Basic Protein / Q000235:genetics*; D009836:Oligodendroglia / Q000502:physiology*; D015345:Oligonucleotide Probes; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D055757:SOXE Transcription Factors; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D004676:Myelin Basic Protein; D015345:Oligonucleotide Probes; D055757:SOXE Transcription Factors; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27