PMID- 10192393
OWN - NLM
STAT- MEDLINE
DCOM- 19990426
LR  - 20220408
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 21
IP  - 4
DP  - 1999 Apr
TI  - A common human skin tumour is caused by activating mutations in beta-catenin.
PG  - 410-3
AB  - WNT signalling orchestrates a number of developmental programs. In response to
      this stimulus, cytoplasmic beta-catenin (encoded by CTNNB1) is stabilized,
      enabling downstream transcriptional activation by members of the LEF/TCF family. 
      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. Most colon cancers arise from mutations in the gene encoding
      adenomatous polyposis coli (APC), a protein required for ubiquitin-mediated
      degradation of beta-catenin, but a small percentage of colon and some other
      cancers harbour beta-catenin-stabilizing mutations. Recently, we discovered that 
      transgenic mice expressing an activated beta-catenin are predisposed to
      developing skin tumours resembling pilomatricomas. 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.
FAU - Chan, E F
AU  - Chan EF
AD  - Howard Hughes Medical Institute, Department of Molecular Genetics and Cell
      Biology, The University of Chicago, Illinois 60637, USA.
FAU - Gat, U
AU  - Gat U
FAU - McNiff, J M
AU  - McNiff JM
FAU - Fuchs, E
AU  - Fuchs E
LA  - eng
GR  - NCI-P50DE/CA-11921/DE/NIDCR NIH HHS/United States
GR  - NIH-RO1-AR31737/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (LEF1 protein, human)
RN  - 0 (Lymphoid Enhancer-Binding Factor 1)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (beta Catenin)
RN  - EC 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific)
RN  - EC 3.1.21.4 (GANTC-specific type II deoxyribonucleases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Cytoskeletal Proteins/*genetics
MH  - DNA-Binding Proteins/analysis/metabolism
MH  - Deoxyribonucleases, Type II Site-Specific/genetics
MH  - Gene Frequency
MH  - Hair Diseases/*genetics/pathology
MH  - Humans
MH  - Lymphoid Enhancer-Binding Factor 1
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Pilomatrixoma/*genetics/pathology
MH  - Polymerase Chain Reaction
MH  - Sequence Analysis, DNA
MH  - Skin Neoplasms/*genetics/pathology
MH  - *Trans-Activators
MH  - Transcription Factors/analysis/metabolism
MH  - beta Catenin
EDAT- 1999/04/07 02:01
MHDA- 2001/03/23 10:01
CRDT- 1999/04/07 02:01
PHST- 1999/04/07 02:01 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/04/07 02:01 [entrez]
AID - 10.1038/7747 [doi]
PST - ppublish
SO  - Nat Genet. 1999 Apr;21(4):410-3. doi: 10.1038/7747.