title: Epidermal hyperplasia and papillomatosis in mice with a keratinocyte-restricted deletion of csk.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering and Orthopaedic Research Center/ND20, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Honda
authors.forename: Takehisa
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.forename: Christian
authors.initials: C
authors.lastname: Schmedt
authors.forename: Angel
authors.initials: A
authors.lastname: Ramirez
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Jorcano
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamisoyama
authors.forename: Takao
authors.initials: T
authors.lastname: Sakai
mesh_terms: 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
chemical_list: D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins