Haploinsufficiency of the cdc21 gene contributes to skin cancer development in mice
Haploinsufficiency of the cdc21 gene contributes to skin cancer development in mice
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DOI：
10.1093/carcin/bgm066
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发表时间：
2007-09-01
期刊：
影响因子：
4.7
通讯作者：
Nelson, Mark A.
中科院分区：
文献类型：
--
作者：
Chandramouli, Anupama;Shi, Jiaqi;Nelson, Mark A.
Cdc2L 基因编码细胞周期蛋白依赖性激酶 11 (CDK11) 蛋白。在几种癌症中观察到 Cdc2L 一个等位基因的缺失和 CDK11 表达的减少，这表明它与癌发生有关。为了直接研究CDK11在致癌作用中的作用，我们首先通过基因捕获技术制备了cdc2l单倍体不足的小鼠，然后研究了这些基因捕获（cdc2l（GT））小鼠对7,12-二甲基苯并[a]蒽（DMBA）/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的化学介导皮肤癌发生的敏感性。两阶段皮肤癌发生模型。野生型和 cdc2l(GT) 小鼠每周两次局部应用 DMBA 启动和 TPA 促进，持续 19 周。第 19 周时，70% 的 cdc2l(GT) 小鼠和 60% 的 cdc2l(+/+) 小鼠出现良性乳头状瘤。然而，与 cdc2l(+/+) 小鼠相比，在 cdc2l(GT) 小鼠中观察到的每只小鼠的平均肿瘤数量总体增加了 3 倍。 cdc2l(GT) 小鼠中较大乳头状瘤的发生率也有所增加。通过聚合酶链反应-限制性片段长度多态性分析，我们在cdc2l(GT)小鼠和cdc2l(+/+)小鼠乳头状瘤组织中发现H-ras基因第61位密码子出现A至T颠换突变。 Ki-67染色显示，与cdc2l(+/+) (30.84%)肿瘤相比，cdc2l(GT) (77.75%) 乳头状瘤的增殖增加。这些研究首次表明，编码 CDK11 的 cdc2l 基因等位基因的缺失会促进 DMBA/TPA 诱导的体内皮肤癌发生。
The Cdc2L gene encodes for the cyclin-dependent kinase 11 (CDK11) protein. Loss of one allele of Cdc2L and reduced CDK11 expression has been observed in several cancers, implicating its association with carcinogenesis. To directly investigate the role of CDK11 in carcinogenesis, we first generated cdc2l haploinsufficient mice by gene trap technology and then studied the susceptibility of these gene-trapped (cdc2l(GT)) mice to chemical-mediated skin carcinogenesis in the 7,12-dimethylbenz[a] anthracene (DMBA)/12-O- tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis model. Wild-type and cdc2l(GT) mice were subjected to a single topical application of initiation by DMBA and promotion twice a week for 19 weeks with TPA. At 19 weeks, 70% of the cdc2l(GT) mice and 60% of the cdc2l(+/+) mice developed benign papillomas. However, there was an overall 3-fold increase in the average number of tumors per mouse observed in cdc2l(GT) mice as compared with cdc2l(+/+) mice. There was also an increased frequency of larger papillomas in cdc2l(GT) mice. By using the polymerase chain reaction - restriction fragment length polymorphism assay, we found A to T transversion mutations at the 61st codon of H-ras gene in the papilloma tissue of both cdc2l(GT) mice and cdc2l(+/+) mice. Ki-67 staining revealed increased proliferation in the papillomas of cdc2l(GT) (77.75%) as compared with cdc2l(+/+) (30.84%) tumors. These studies are the first to show that loss of one allele of cdc2l gene, encoding CDK11, facilitates DMBA/TPA-induced skin carcinogenesis in vivo.