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| A common human skin tumour is caused by activating mutations in beta-catenin |
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| Author(s): Chan EF, Gat U, McNiff JM, Fuchs E |
| Source: NATURE GENETICS Volume: 21 Issue: 4 Pages: 410-413 Published: APR 1999 |
| Times Cited: 297 References: 30 |
| Abstract: WNT signalling orchestrates a number of developmental programs(1-3), In response to this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized, enabling downstream transcriptional activation by members of the LEF/TCF family(4,5). One of the target genes for beta-catenin/TCF encodes c-MYC, explaining why constitutive activation of the WNT pathway can lead to cancer, particularly in the colon(6). Most colon cancers arise from mutations in the gene encoding adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated degradation of beta-catenin(7), but a small percentage of colon and some other cancers harbour beta-catenin-stabilizing mutations (refs 8-17). Recently, we discovered that transgenic mice expressing an activated beta-catenin are predisposed to developing skin tumours resembling pilomatricoma(18). Given that the skin of these adult mice also exhibits signs of de novo hair-follicle morphogenesis, we wondered whether human pilomatricomas might originate from hair matrix cells and whether they might possess beta-catenin-stabilizing mutations. Here, we explore the cell origin and aetiology of this common human skin tumour. We found nuclear LEF-1 in the dividing tumour cells, providing biochemical evidence that pilomatricomas are derived from hair matrix cells. At least 75% of these tumours possess mutations affecting the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation of the protein. This percentage of CTNNB1 mutations is greater than in all other human tumours examined thus far, and directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans. |
| Document Type: Article |
| Language: English |
| Reprint Address: Fuchs, E (reprint author), Univ Chicago, Howard Hughes Med Inst, Dept Mol Genet & Cell Biol, 5841 S Maryland Ave, Chicago, IL 60637 USA |
Addresses:
1. Univ Chicago, Howard Hughes Med Inst, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA
2. Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA |
| Publisher: NATURE AMERICA INC, 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA |
| Subject Category: Genetics & Heredity |
| IDS Number: 181KC |
| ISSN: 1061-4036 |
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