Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression.
We have generated mice with a floxed fak allele under the control of keratin-14-driven Cre fused to a modified estrogen receptor (CreER(T2)). 4-Hydroxy-tamoxifen treatment induced fak deletion in the epidermis, and suppressed chemically induced skin tumor formation. Loss of fak induced once benign tumors had formed inhibited malignant progression. Although fak deletion was associated with reduced migration of keratinocytes in vitro, we found no effect on wound re-epithelialization in vivo. However, increased keratinocyte cell death was observed after fak deletion in vitro and in vivo. Our work provides the first experimental proof implicating FAK in tumorigenesis, and this is associated with enhanced apoptosis.
McLean
Gordon W
GW
The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, G61 1BD, United Kingdom. g.mclean@beatson.gla.ac.uk
Komiyama
Noboru H
NH
Serrels
Bryan
B
Asano
Hidefumi
H
Reynolds
Louise
L
Conti
Francesco
F
Hodivala-Dilke
Kairbaan
K
Metzger
Daniel
D
Chambon
Pierre
P
Grant
Seth G N
SG
Frame
Margaret C
MC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D017931:DNA Primers; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017353:Gene Deletion; D005838:Genotype; D006915:Hydroxytestosterones / Q000378:metabolism; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D053547:Keratin-14; D015603:Keratinocytes / Q000502:physiology; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
D017931:DNA Primers; D006915:Hydroxytestosterones; D053547:Keratin-14; C507446:Krt14 protein, mouse; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; C032278:4,17 beta-dihydroxy-4-androstene-3-one; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; C045073:Cre recombinase; D019426:Integrases