Epidermal hyperplasia and papillomatosis in mice with a keratinocyte-restricted deletion of csk.
The Src family kinases (SFKs) are believed to play critical roles in malignant transformation, as well as in growth, invasion and dissemination of neoplastic tissue. Inhibition of SFK-mediated signal transduction and activation of downstream targets inhibits tumor progression. To determine whether constitutive activity of SFK per se is sufficient to induce tumorigenesis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of the SFK-negative regulator csk (Csk-K5 mice). Even though expression levels of SFKs were lower in C-terminal Src kinase (Csk)-null keratinocytes, activity levels were higher than in control keratinocytes. At the age of 3 months, all Csk-K5 mice displayed signs of chronic inflammation in dermis and epidermal hyperplasia. About 19% of Csk-K5 mice (7 out of 36) developed papillomatous lesions. However, these lesions did not show any signs of neoplastic transformation over the next 8 months. Epidermal hyperplasia and hyperkeratosis in Csk-K5 mice were associated with an increased number of stem cells in the interfollicular epidermis, an increased proliferation of basal keratinocytes and a delayed terminal differentiation of the suprabasal keratinocytes. Our results clearly demonstrate that even though SFK-mediated signaling promotes tumor progression, elevated activity of SFKs in vivo alone is not sufficient to induce neoplastic transformation.
Honda
Kazuhisa
K
Department of Biomedical Engineering and Orthopaedic Research Center/ND20, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Sakaguchi
Takehisa
T
Sakai
Keiko
K
Schmedt
Christian
C
Ramirez
Angel
A
Jorcano
Jose Luis
JL
Tarakhovsky
Alexander
A
Kamisoyama
Hiroshi
H
Sakai
Takao
T
D000818:Animals; D000831:Animals, Newborn; D004817:Epidermis / Q000473:pathology*; D017353:Gene Deletion; D006965:Hyperplasia; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D010212:Papilloma / Q000235:genetics / Q000473:pathology*; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D014947:Wounds and Injuries / Q000473:pathology / Q000503:physiopathology
D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins