Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues
Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues
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DOI：
10.1128/mcb.24.17.7538-7547.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Rodriguez-Puebla, ML
中科院分区：
文献类型：
--
作者：
de Marval, PLM;Macias, E;Rodriguez-Puebla, ML
原癌基因c-myc编码一种转录因子，该转录因子参与细胞增殖、分化和凋亡的调节，并且还发现其在几种形式的人类和实验性肿瘤中失调。我们已经表明，在转基因小鼠（K5-Myc）的上皮组织中强制表达c-myc导致角质形成细胞过度增殖和皮肤和口腔中自发性肿瘤的发展。尽管许多参与癌症发展的基因都受到c-myc的调节，但导致Myc诱导的瘤形成的实际机制尚不清楚。在Myc调控的基因中有细胞周期蛋白依赖性激酶4（CDK 4）基因。有趣的是，我们实验室以前的研究表明，CDK 4的过度表达导致角质形成细胞过度增殖，尽管没有观察到自发的肿瘤发展。因此，我们验证了CDK 4可能是参与Myc致癌作用的关键下游基因之一的假设。我们的研究结果表明，在K5-Myc转基因小鼠中，CDK 4抑制导致肿瘤发展的完全抑制，这表明CDK 4是由失调的Myc诱导的肿瘤形成的关键介质。此外，与K5-Myc同窝出生的小鼠相比，CDK 4表达的缺乏导致表皮厚度和角质形成细胞增殖显著降低。K5-Myc表皮的生化分析表明，CDK 4通过隔离p21（Cip 1）和p27（Kip 1）介导Myc的增殖活性，从而间接激活CDK 2激酶活性。这些结果表明，CDK 4介导的增殖和致癌活性的Myc在体内通过一种机制，涉及螯合的特异性CDK抑制剂。
The proto-oncogene c-myc encodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis and that has also been found to be deregulated in several forms of human and experimental tumors. We have shown that forced expression of c-myc in epithelial tissues of transgenic mice (K5-Myc) resulted in keratinocyte hyperproliferation and the development of spontaneous tumors in the skin and oral cavity. Although a number of genes involved in cancer development are regulated by c-myc, the actual mechanisms leading to Myc-induced neoplasia are not known. Among the genes regulated by Myc is the cyclin-dependent kinase 4 (CDK4) gene. Interestingly, previous studies from our laboratory showed that the overexpression of CDK4 led to keratinocyte hyperproliferation, although no spontaneous tumor development was observed. Thus, we tested the hypothesis that CDK4 may be one of the critical downstream genes involved in Myc carcinogenesis. Our results showed that CDK4 inhibition in K5-Myc transgenic mice resulted in the complete inhibition of tumor development, suggesting that CDK4 is a critical mediator of tumor formation induced by deregulated Myc. Furthermore, a lack of CDK4 expression resulted in marked decreases in epidermal thickness and keratinocyte proliferation compared to the results obtained for K5-Myc littermates. Biochemical analysis of the K5-Myc epidermis showed that CDK4 mediates the proliferative activities of Myc by sequestering p21(Cip1) and p27(Kip1) and thereby indirectly activating CDK2 kinase activity. These results show that CDK4 mediates the proliferative and oncogenic activities of Myc in vivo through a mechanism that involves the sequestration of specific CDK inhibitors.