Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

A common human skin tumour is caused by activating mutations in β-catenin

A common human skin tumour is caused by activating mutations in β-catenin WNT signalling orchestrates a number of developmental programs 1,2,3 . In response to this stimulus, cytoplasmic β-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 β-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 β-catenin 7 , but a small percentage of colon and some other cancers harbour β-catenin–stabilizing mutations (refs 8,9,10,11, 12,13,14,15,16, 17). Recently, we discovered that transgenic mice expressing an activated β-catenin are predisposed to developing skin tumours resembling pilomatricomas 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 β-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 β-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Genetics Springer Journals

A common human skin tumour is caused by activating mutations in β-catenin

Download PDF
4 pages

Loading next page...
 
/lp/springer-journals/a-common-human-skin-tumour-is-caused-by-activating-mutations-in-qPOLdeFGvf

References (32)

Publisher
Springer Journals
Copyright
Copyright © 1999 by Nature America Inc.
Subject
Biomedicine; Biomedicine, general; Human Genetics; Cancer Research; Agriculture; Gene Function; Animal Genetics and Genomics
ISSN
1061-4036
eISSN
1546-1718
DOI
10.1038/7747
Publisher site
See Article on Publisher Site

Abstract

WNT signalling orchestrates a number of developmental programs 1,2,3 . In response to this stimulus, cytoplasmic β-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 β-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 β-catenin 7 , but a small percentage of colon and some other cancers harbour β-catenin–stabilizing mutations (refs 8,9,10,11, 12,13,14,15,16, 17). Recently, we discovered that transgenic mice expressing an activated β-catenin are predisposed to developing skin tumours resembling pilomatricomas 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 β-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 β-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.

Journal

Nature Genetics – Springer Journals

Published: Apr 1, 1999

There are no references for this article.