D'Armiento J, DiColandrea T, Dalal S S, Okada Y, Huang M T, Conney A H, Chada K
Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
Mol Cell Biol. 1995 Oct;15(10):5732-9. doi: 10.1128/MCB.15.10.5732.
In a series of transgenic mice, the human tissue collagenase gene was expressed in the suprabasal layer of the skin epidermis. Visually, the mice had dry and scaly skin which upon histological analysis revealed acanthosis, hyperkeratosis, and epidermal hyperplasia. At the ultrastructural level, intercellular granular materials were absent in the transgenic skin epidermis but contact was maintained through the intact desmosomes. Despite a diversity of underlying etiologies, similar morphological hyperproliferative changes in the epidermis are observed in the human skin diseases of lamellar ichthyosis, atopic dermatitis, and psoriasis. Subsequent experiments demonstrate that when the transgenic mouse skin was treated once with an initiator (7,12-dimethyl-benz[a]anthracene) and then twice weekly with a promoter (12-O-tetradecanoylphorbol-13-acetate), there was a marked increase in tumor incidence among transgenic mice compared with that among control littermates. These experiments demonstrate that by overexpressing the highly specific proteolytic enzyme collagenase, a cascade of events leading to profound morphological changes which augment the sensitivity of the skin towards carcinogenesis is initiated in the epidermis.
在一系列转基因小鼠中，人类组织胶原酶基因在皮肤表皮的基底层上层表达。从外观上看，这些小鼠的皮肤干燥且有鳞屑，组织学分析显示有棘层肥厚、角化过度和表皮增生。在超微结构水平上，转基因皮肤表皮中不存在细胞间颗粒物质，但通过完整的桥粒维持细胞间联系。尽管潜在病因多种多样，但在板层状鱼鳞病、特应性皮炎和银屑病等人类皮肤疾病中，表皮会出现类似的形态学增生性变化。随后的实验表明，当转基因小鼠皮肤先用一种引发剂（7,12 - 二甲基苯并[a]蒽）处理一次，然后每周用一种促进剂（12 - O - 十四酰佛波醇 - 13 - 乙酸酯）处理两次时，与对照同窝小鼠相比，转基因小鼠的肿瘤发生率显著增加。这些实验表明，通过过度表达高度特异性的蛋白水解酶胶原酶，在表皮中引发了一系列导致深刻形态学变化的事件，这些变化增强了皮肤对致癌作用的敏感性。
