Transgenic expression of cyclin-dependent kinase 4 results in epidermal hyperplasia, hypertrophy, and severe dermal fibrosis

被引:34
作者
de Marval, PLM
Gimenez-Conti, IB
LaCava, M
Martinez, LA
Conti, CJ
Rodriguez-Puebla, ML [1 ]
机构
[1] Univ Texas, MD Anderson Hosp & Tumor Inst, Sci Pk Res Div, Smithville, TX 78957 USA
[2] Univ Texas, MD Anderson Hosp & Tumor Inst, Dept Carcinogenesis, Smithville, TX 78957 USA
关键词
D O I
10.1016/S0002-9440(10)61703-8
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
In a previous report we have described the effects of expression of D-type cyclins in epithelial tissues of transgenic mice. To study the involvement of the D-type cyclin partner cyclin-dependent kinase 4 (CDK4) In epithelial growth and differentiation, transgenic mice were generated carrying the CDK4 gene under the control of a keratin 5 promoter. As expected, transgenic mice showed expression of CDK4 in the epidermal basal-cell layer. Epidermal proliferation increased dramatically and basal cell hyperplasia and hypertrophy were observed. The hyperproliferative phenotype of these transgenic mice was independent of D-type cyclin expression because no overexpression of these proteins was detected. CDK4 and CDK2 kinase activities increased in transgenic animals and were associated with elevated binding of p27(Kip1) to CDK4. Expression of CDK4 in the epidermis results in an increased spinous layer compared with normal epidermis, and a mild hyperkeratosis in the cornified layer. In addition to epidermal changes, severe dermal fibrosis was observed and part of the subcutaneous adipose tissue was replaced by connective tissue. Also, abnormal expression of keratin 6 associated with the hyperproliferative phenotype was observed in transgenic epidermis. This model provides in vivo evidence for the rot of CDK4 as a mediator of proliferation in epithelial cells independent of D-type cyclin expression.
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页码:369 / 379
页数:11
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