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First published online 5 August 2003
doi: 10.1242/jcs.00725
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Research Article |
6ß4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFß signalling
1 Keratinocyte Laboratory, CR-UK London Research Institute, 44 Lincoln's Inn
Fields, London WC2A 3PX, UK
2 Pfizer Global Research and Development, Sandwich Data Centre, Sandwich CT13
9NJ, UK
Author for correspondence (e-mail:
fiona.watt{at}cancer.org.uk)
Accepted 24 June 2003
Inappropriate 
6ß4 integrin expression correlates with a high
risk of tumour progression in stratified squamous epithelia. Targeted
expression of 6ß4 in the suprabasal layers of transgenic mouse
epidermis dramatically increased the frequency of papillomas, carcinomas and
metastases induced by chemical carcinogenesis, independent of the ß4
cytoplasmic domain. Suprabasal 6ß4 also perturbed transforming
growth factor ß (TGFß) signalling as demonstrated by decreased
nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes,
suprabasal 6ß4 relieved TGFß-mediated growth inhibition and
blocked nuclear translocation of activated Smad2/3. Responsiveness to
TGFß could be restored by inhibiting cadherin-mediated cell-cell adhesion
or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting
mitogen-activated protein kinase (MAPK) activity. These data suggest that
suprabasal 6ß4 promotes tumourigenesis by preventing TGFß
from suppressing clonal expansion of initiated cells in the epidermal basal
layer.
Key words: Keratinocyte, Differentiation, Carcinogenesis, Skin, Smad
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4ß6 and TGFß at odds in tumorigenesis
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