Role of neurofibromin in modulation of expression of the tyrosinase-related protein 2 gene.
Tyrosinase-related protein 2 (TRP-2)/DOPAchrome tautomerase is an enzyme involved in melanin biosynthesis and plays an important role in cytoprotection by preventing the production of a toxic melanin precursor, 5,6-dihydroxyindole. Neurofibromin is the protein product of a gene linked to neurofibromatosis type 1 (NF1), which is characterized by multiple neurofibromas and abnormalities in skin pigmentation. To explore the pathogenesis of NF1, we studied the role of neurofibromin in the regulation of TRP-2 gene expression. By means of transient cotransfection assays, we show that the expression of a reporter gene under the control of the TRP-2 gene promoter was increased by a neurofibromin-dependent signal through the 71-bp region (positions -415 to -345). A Lys-to-Glu substitution at position 1425 in neurofibromin abrogated this activating function. A dominant negative Ki-ras inhibitor mimics neurofibromin's function, and additively increases TRP-2 promoter activity when coexpressed with neurofibromin. Therefore, we suggest that neurofibromin is involved in the regulation of TRP-2 gene expression. Moreover, we found a single case of a glioblastoma multiforme that expresses TRP-2 mRNA but not tyrosinase mRNA, suggesting that TRP-2 may function in human neural tissues under certain conditions.
Suzuki
H
H
Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
Takahashi
K
K
Yasumoto
K
K
Amae
S
S
Yoshizawa
M
M
Fuse
N
N
Shibahara
S
S
D000818:Animals; D001483:Base Sequence; D004247:DNA; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008969:Molecular Sequence Data; D025542:Neurofibromin 1; D011401:Promoter Regions, Genetic; D021382:Protein Sorting Signals; D011506:Proteins / Q000502:physiology*; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
D025542:Neurofibromin 1; D021382:Protein Sorting Signals; D011506:Proteins; D004247:DNA; D018631:ras Proteins; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase