Cooperative action of germ-line mutations in decorin and p53 accelerates lymphoma tumorigenesis
Cooperative action of germ-line mutations in decorin and p53 accelerates lymphoma tumorigenesis
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DOI：
10.1073/pnas.96.6.3092
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Eichstetter, I
中科院分区：
文献类型：
--
作者：
Iozzo, RV;Chakrani, F;Eichstetter, I
Decorin在多种转化细胞中的异位表达会导致裸鼠的生长停滞和无法在裸鼠体内产生肿瘤，这一过程是由Decorin介导的表皮生长因子受体激活引起的，从而导致内源性p21(WAF1.CIP1)(周期蛋白依赖性激酶抑制物p21)的持续诱导和生长停滞。然而，定向破坏核心蛋白聚糖基因的小鼠不会患上自发性肿瘤，为了测试核心蛋白蛋白在肿瘤发生中的作用，我们产生了同时缺乏核心蛋白聚糖和p53的小鼠，P53是一种已建立的肿瘤抑制基因。缺乏这两种基因的小鼠表现出更快的肿瘤发展速度，并在6个月内几乎一致地死于胸腺淋巴瘤[平均存活年龄(T-50)类似于4个月]，携带一个Decorin等位基因且没有p53基因的小鼠患上与双基因敲除动物相同的肿瘤谱，但存活率与p53基因敲除动物相似(T-50类似于6个月)。从双突变动物分离的胸腺淋巴瘤细胞中异位表达核心蛋白核心蛋白显著抑制其集落形成能力。当这些淋巴瘤细胞与来自野生型或核心蛋白聚糖缺失胚胎的成纤维细胞共同培养时，细胞在没有核心蛋白聚糖的情况下生长较快，而且外源性核心蛋白多糖或其蛋白核心在体外显著抑制了细胞的生长。这些结果表明，在易患癌症的小鼠模型中，核心蛋白聚糖的缺乏是允许淋巴瘤发生的原因，并表明核心蛋白核心蛋白和p53的胚系突变可能在淋巴细胞的转化中协同作用，并最终通过缩短肿瘤潜伏期而导致更具侵袭性的表型。
Ectopic expression of decorin in a wide variety of transformed cells results in growth arrest and the inability to generate tumors in nude mice, This process is caused by a decorin-mediated activation of the epidermal growth factor receptor, which leads to a sustained induction of endogenous p21(WAF1.CIP1) (the cyclin-dependent kinase inhibitor p21) and growth arrest. However, mice harboring a targeted disruption of the decorin gene do not develop spontaneous tumors, To test the role of decorin in tumorigenesis, we generated mice lacking both decorin and p53, an established tumor-suppressor gene. Mice lacking both genes showed a faster rate of tumor development and succumbed almost uniformly to thymic lymphomas within 6 months [mean survival age (T-50) similar to 4 months], Mice harboring one decorin allele and no p53 gene developed the same spectrum of tumors as the double knockout animals, but had a survival rate similar to the p53 nub animals (T-50 similar to 6 months). Ectopic expression of decorin in thymic lymphoma cells isolated from double mutant animals markedly suppressed their colony-forming ability. When these lymphoma cells were cocultured wit fibroblasts derived from either wild-type or decorin null embryos, the cells grew faster in the absence of decorin, Moreover, exogenous decorin proteoglycan or its protein core significantly retarded their growth in vitro. These results indicate that the lack of decorin is permissive for lymphoma tumorigenesis in a mouse model predisposed to cancer and suggest that germ-line mutations in decorin and p53 may cooperate in the transformation of lymphocytes and ultimately lead to a more aggressive phenotype by shortening the tumor latency.