Decreased focal adhesion kinase suppresses papilloma formation during experimental mouse skin carcinogenesis.
Although focal adhesion kinase (FAK) is elevated in epithelial cancers, it is not known whether FAK expression influences tumor development in vivo. We found that fak +/- heterozygous mice display reduced 7,12-dimethylbenz[a]anthracene-induced papilloma formation that correlates with reduced FAK protein expression in the skin. However, the frequency of malignant conversion of papillomas into carcinomas is indistinguishable in fak +/- mice and their wild-type fak +/+ littermates, most likely because papilloma FAK protein expression is elevated to wild-type levels. We also found that keratinocyte FAK protein expression is important for cellular responses downstream of ras in vitro (monitored by extracellular signal-regulated kinase activation after integrin engagement). Because 7,12-dimethylbenz[a]anthracene induces an activating mutation of H-ras, this provides one possible explanation for suppression of papilloma formation when FAK protein is limiting.
McLean
G W
GW
Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow G61 1BD, United Kingdom.
Brown
K
K
Arbuckle
M I
MI
Wyke
A W
AW
Pikkarainen
T
T
Ruoslahti
E
E
Frame
M C
MC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018628:Gene Dosage; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D018631:ras Proteins / Q000502:physiology
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D018631:ras Proteins