Aggeler J, Murnane J P
Laboratory of Radiobiology and Environmental Health, University of California, San Francisco 94143.
In Vitro Cell Dev Biol. 1990 Sep;26(9):915-22. doi: 10.1007/BF02624617.
Ataxia-telangiectasia and xeroderma pigmentosum are human hereditary diseases in which patients are cancer prone and demonstrate increased sensitivity to DNA damage by ionizing and ultraviolet radiation, respectively. In culture, both ataxia-telangiectasia and xeroderma pigmentosum skin fibroblasts show increased synthesis and secretion of the extracellular matrix proteins fibronectin and collagen. To determine whether these differences in protein production result from fundamental abnormalities in regulation of genes associated with cellular interactions, we compared the effects of trifluoperazine and 12-O-tetradecanoylphorbol-13-acetate on expression of the extracellular matrix-degrading metalloproteinases, procollagenase and prostromelysin, by normal, ataxia-telangiectasia, and xeroderma pigmentosum fibroblasts. After trifluoperazine treatment the overall levels of these metalloproteinases were much greater in three ataxia-telangiectasia cell strains and in cells from xeroderma pigmentosum complementation groups A and D than in normal cells. In contrast, cells from xeroderma pigmentosum complementation group C produced only slightly more procollagenase than normal cells. 12-O-tetradecanoylphorbol-13-acetate also induced higher than normal levels of procollagenase in some ataxia-telangiectasia and xeroderma pigmentosum strains, but less than that induced by trifluoperazine. Because increased extracellular accumulation of matrix-degrading enzymes has long been implicated in metastatic progression, this altered expression of procollagenase and prostromelysin in ataxia-telangiectasia and xeroderma pigmentosum cells could play an important role in the pathogenesis of various tumors in individuals with these genetic diseases.
共济失调毛细血管扩张症和着色性干皮病是人类遗传性疾病，患有这两种疾病的患者容易患癌症，并且分别表现出对电离辐射和紫外线造成的DNA损伤更为敏感。在培养过程中，共济失调毛细血管扩张症和着色性干皮病的皮肤成纤维细胞均表现出细胞外基质蛋白纤连蛋白和胶原蛋白的合成及分泌增加。为了确定这些蛋白质产生的差异是否源于与细胞相互作用相关基因调控的根本异常，我们比较了三氟拉嗪和12 - O - 十四酰佛波醇 - 13 - 乙酸酯对正常、共济失调毛细血管扩张症和着色性干皮病成纤维细胞中细胞外基质降解金属蛋白酶、前胶原酶和前基质溶解素表达的影响。用三氟拉嗪处理后，这三种金属蛋白酶在三个共济失调毛细血管扩张症细胞株以及着色性干皮病互补组A和D的细胞中的总体水平比正常细胞中高得多。相比之下，着色性干皮病互补组C的细胞产生的前胶原酶仅比正常细胞略多。12 - O - 十四酰佛波醇 - 13 - 乙酸酯在一些共济失调毛细血管扩张症和着色性干皮病细胞株中也诱导产生高于正常水平的前胶原酶，但低于三氟拉嗪诱导的水平。由于基质降解酶在细胞外的积累增加长期以来一直被认为与转移进展有关，因此共济失调毛细血管扩张症和着色性干皮病细胞中前胶原酶和前基质溶解素的这种表达改变可能在患有这些遗传疾病的个体发生各种肿瘤的发病机制中起重要作用。
