Breitenbach U, Tuckermann J P, Gebhardt C, Richter K H, Fürstenberger G, Christofori G, Angel P
Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
J Invest Dermatol. 2001 Sep;117(3):634-40. doi: 10.1046/j.0022-202x.2001.01437.x.
Malignant transformation of mouse skin by chemical carcinogens and tumor promoters, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, is a multistage process leading to the formation of squamous cell carcinomas. In an effort to identify target genes whose expression is associated with skin tumorigenesis we combined elements of suppression subtractive hybridization with differential screening to isolate genes that are differentially upregulated in mouse skin after short-term treatment with 12-O-tetradecanoylphorbol-13-acetate and that exhibit a high constitutive expression in squamous cell carcinomas. Here, we report the detailed analysis of one of these cDNAs encoding the serine protease BSSP in mouse skin. Phorbol ester application increases BSSP expression in keratinocytes of the epidermis and the hair follicle several-fold starting 4 h post- treatment. Transcriptional activation of BSSP by 12-O-tetradecanoylphorbol-13-acetate was found to be independent of c-Fos expression and resistant to downregulation by glucocorticoids. By monitoring BSSP expression throughout experimental skin carcinogenesis we found strong constitutive expression in hyperplastic epidermis as well as in proliferatively active keratinocytes of benign and malignant skin tumors. These results establish a novel link between expression of an as yet ill-defined serine protease and skin carcinogenesis.
化学致癌物和肿瘤促进剂（如佛波酯12 - O -十四烷酰佛波醇-13 -乙酸酯）诱导小鼠皮肤发生恶性转化是一个多阶段过程，最终导致鳞状细胞癌的形成。为了鉴定那些表达与皮肤肿瘤发生相关的靶基因，我们将抑制性消减杂交技术与差异筛选相结合，以分离在用12 - O -十四烷酰佛波醇-13 -乙酸酯短期处理后的小鼠皮肤中差异上调且在鳞状细胞癌中呈高组成性表达的基因。在此，我们报告对其中一个编码小鼠皮肤丝氨酸蛋白酶BSSP的cDNA的详细分析。施用佛波酯后4小时起，表皮和毛囊角质形成细胞中BSSP的表达增加数倍。发现12 - O -十四烷酰佛波醇-13 -乙酸酯对BSSP的转录激活独立于c - Fos的表达，并且对糖皮质激素的下调具有抗性。通过监测整个实验性皮肤致癌过程中BSSP的表达，我们发现在增生性表皮以及良性和恶性皮肤肿瘤的增殖活跃角质形成细胞中均有强组成性表达。这些结果在一种尚未明确的丝氨酸蛋白酶的表达与皮肤致癌作用之间建立了新的联系。
