F-box and WD repeat domain-containing 7 regulates intestinal cell lineage commitment and is a haploinsufficient tumor suppressor.
OBJECTIVE
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.
Sancho
Rocio
R
Mammalian Genetics Laboratory, CR UK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK.
Jandke
Anett
A
Davis
Hayley
H
Diefenbacher
Markus E
ME
Tomlinson
Ian
I
Behrens
Axel
A
D011125:Adenomatous Polyposis Coli / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017491:Genes, APC; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D044767:Ubiquitin-Protein Ligases