title: Development of transgenic mice that inducibly express an active form of c-Src in the epidermis.
abstract: Recent work from our laboratory has shown that elevated src kinase activity enhances tumor promotion, malignant progression, and metastasis during multistage skin carcinogenesis. In this study, we have generated "gene-switch" src(530) transgenic mice to further analyze the role of this nonreceptor tyrosine kinase in multistage carcinogenesis. Target transgenic mice that have an activated form of the human c-src (src(530)) gene fused with GAL4 binding sites upstream of the thymidine kinase (TK) promoter were generated. Two lines of epidermis-specific transactivator mice were used that targeted the expression of GLVPc or GLp65 transactivators, fusion molecules containing a truncated progesterone receptor with a GAl4-DNA binding domain, with either a mouse loricrin (ML) or human keratin 14 (HK14) promoter, respectively. The transactivator mice (ML.GLVPc or HK14.GLp65) and the target mice (TK.src(530)) were mated to generate bitransgenic mice, and src(530) transgene expression was induced by topical application of RU486 (mifepristone, a progesterone receptor antagonist). In both ML.GLVPc/TK.src(530) and HK14.GLp65/TK.src(530) bitransgenic mice, histological analysis revealed that only the bitransgenic mice had marked epidermal hyperplasia and hyperkeratosis after treatment with RU486. Neither the nontransgenic mice nor the mice hemizygous for either the transactivator transgene or the target transgene alone showed any response to treatment with RU486. In addition, no differences were observed in the skin of the bitransgenic mice versus nontransgenic littermates without treatment of RU486. Interestingly, in HK14.GLp65/TK.src(530) bitransgenic mice, squamous cell carcinomas (SCCs) arose along the periphery of the area of the punch biopsies in 25% of the bitransgenic mice several weeks after taking the biopsy and subsequent to RU486 treatment. Collectively, the data support a role of c-src activation in epidermal hyperproliferation. Furthermore, the data support the conclusion that src activation can substitute for an initiating event in the presence of a tumor promoting stimulus (i.e., wounding). Finally, inducible src(530) transgenic mice provide a new tool for dissecting the role of src activation in multistage carcinogenesis by allowing temporal control of the expression of this oncogene.
authors.affiliation: Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kiguchi
authors.forename: Jianghong
authors.initials: J
authors.lastname: Jiang
authors.forename: Steve
authors.initials: S
authors.lastname: Carbajal
authors.forename: Lynnsie
authors.initials: L
authors.lastname: Ruffino
authors.forename: Linda
authors.initials: L
authors.lastname: Beltrán
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D006727:Hormone Antagonists; D015735:Mifepristone; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human