PMID- 20638938
OWN - NLM
STAT- MEDLINE
DCOM- 20100920
LR  - 20171116
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 139
IP  - 3
DP  - 2010 Sep
TI  - F-box and WD repeat domain-containing 7 regulates intestinal cell lineage 
      commitment and is a haploinsufficient tumor suppressor.
PG  - 929-41
LID - 10.1053/j.gastro.2010.05.078 [doi]
AB  - BACKGROUND & AIMS: The E3 ubiquitin ligase F-box and WD repeat domain-containing 
      7 (Fbw7) degrades several proto-oncogenes including c-Myc, cyclinE, Notch1, and 
      c-Jun. Fbw7 is the fourth most frequently mutated gene in human colorectal 
      carcinomas and has recently been described as a poor prognosis marker in human 
      colorectal carcinoma; however, the molecular mechanism underlying fbw7 mutations 
      in intestinal tumor suppression is unclear. METHODS: To address the role of fbw7 
      in intestinal homeostasis and tumorigenesis, we generated conditional knock-out 
      mice lacking fbw7 in the intestine and evaluated the effect of fbw7 absence in 
      normal intestinal homeostasis and in adenomatous polyposis coli-mediated 
      tumorigenesis. In parallel, we analyzed a cohort of human tumors bearing 
      mutations in fbw7. RESULTS: Fbw7 was found to be highly expressed in the 
      transit-amplifying progenitor cell compartment, and its deletion resulted in 
      impaired goblet cell differentiation and accumulation of highly proliferating 
      progenitor cells. This function of Fbw7 was mirrored during tumor formation 
      because absence of Fbw7 increased proliferation and decreased differentiation of 
      tumors triggered by aberrant Wnt signalling. Fbw7 exhibited haploinsufficiency 
      for intestinal tumor suppression. Biallelic fbw7 inactivation increased cellular 
      proliferation in physiologic and pathologic conditions in a c-Jun-dependent 
      manner. Increased Notch activity was also observed in human tumors carrying 
      heterozygous fbw7 mutations, suggesting that fbw7 haploinsufficiency for 
      antagonizing Notch activity is conserved between human and murine cancers. 
      CONCLUSIONS: Fbw7 regulates intestinal biology and tumorigenesis by controlling 
      the abundance of different substrates in a dose-dependent fashion, providing a 
      molecular explanation for the heterozygous mutations of fbw7 observed in human 
      colorectal carcinoma.
CI  - Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Sancho, Rocio
AU  - Sancho R
AD  - Mammalian Genetics Laboratory, CR UK London Research Institute, Lincoln's Inn 
      Fields Laboratories, London, UK.
FAU - Jandke, Anett
AU  - Jandke A
FAU - Davis, Hayley
AU  - Davis H
FAU - Diefenbacher, Markus E
AU  - Diefenbacher ME
FAU - Tomlinson, Ian
AU  - Tomlinson I
FAU - Behrens, Axel
AU  - Behrens A
LA  - eng
GR  - Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100602
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (F-Box Proteins)
RN  - 0 (F-Box-WD Repeat-Containing Protein 7)
RN  - 0 (FBXW7 protein, human)
RN  - 0 (Fbxw7 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (Receptors, Notch)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Wnt Proteins)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Adenomatous Polyposis Coli/metabolism/pathology
MH  - Animals
MH  - Carcinoma/genetics/*metabolism/pathology
MH  - Cell Cycle Proteins/genetics/*metabolism
MH  - Cell Differentiation
MH  - *Cell Lineage
MH  - Cell Proliferation
MH  - Colorectal Neoplasms/genetics/*metabolism/pathology
MH  - F-Box Proteins/genetics/*metabolism
MH  - F-Box-WD Repeat-Containing Protein 7
MH  - Genes, APC
MH  - Haplotypes
MH  - Heterozygote
MH  - Humans
MH  - Intestinal Mucosa/*metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Mutation
MH  - Proto-Oncogene Proteins c-jun/metabolism
MH  - Receptors, Notch/metabolism
MH  - Signal Transduction
MH  - Stem Cells/*metabolism/pathology
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism
MH  - Wnt Proteins/metabolism
EDAT- 2010/07/20 06:00
MHDA- 2010/09/21 06:00
CRDT- 2010/07/20 06:00
PHST- 2010/01/05 00:00 [received]
PHST- 2010/05/17 00:00 [revised]
PHST- 2010/05/25 00:00 [accepted]
PHST- 2010/07/20 06:00 [entrez]
PHST- 2010/07/20 06:00 [pubmed]
PHST- 2010/09/21 06:00 [medline]
AID - S0016-5085(10)00840-1 [pii]
AID - 10.1053/j.gastro.2010.05.078 [doi]
PST - ppublish
SO  - Gastroenterology. 2010 Sep;139(3):929-41. doi: 10.1053/j.gastro.2010.05.078. Epub 
      2010 Jun 2.