Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss.
Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss.
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DOI：
10.1158/0008-5472.can-10-0315
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Sansom OJ
中科院分区：
文献类型：
--
作者：
Cole AM;Myant K;Reed KR;Ridgway RA;Athineos D;Van den Brink GR;Muncan V;Clevers H;Clarke AR;Sicinski P;Sansom OJ
Apc基因的失活被认为是散发性结直肠癌发展中的关键早期事件，其中Apc基因的缺失导致β-连环蛋白/TCF 4信号传导的组成性激活，从而导致Wnt靶基因如c-Myc的转录。我们和其他先前的研究表明，虽然细胞周期蛋白D1是腺瘤形成所必需的，但在肠内Apc丢失后，它不会立即上调，这表明急性Apc丢失后的增殖可能依赖于另一种D型细胞周期蛋白。在这项研究中，我们研究了细胞周期蛋白D2的表达和功能的相关性后，在肠上皮细胞的APC损失。细胞周期蛋白D2在Apc丧失后立即上调，这与CDK 4和过度磷酸化Rb水平的显著增加相对应。细胞周期蛋白D2的缺乏导致肠上皮细胞增殖减少和隐窝大小在APC缺陷的肠上皮。此外，细胞周期蛋白D2显着降低ApcMin/+小鼠中的肿瘤生长和发育。重要的是，细胞周期蛋白D2敲除不影响正常肠上皮细胞的增殖，此外，CDK 4/6抑制也抑制腺瘤细胞的增殖，而不是来自ApcMin/+小鼠的正常细胞。总之，这些结果表明，细胞周期蛋白D-CDK 4/6复合物是Wnt信号转导失调的细胞有效增殖所必需的，抑制这种复合物可能是结直肠癌的有效化学预防策略。
Inactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer where its loss leads to constitutive activation of β-catenin/TCF4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and others previous studies have shown that although Cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting proliferation following acute Apc loss may be dependent on another D-type Cyclin. In this study we investigated the expression and functional relevance of Cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in CDK4 and hyper-phosphorylated Rb levels. Deficiency of Cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc deficient intestinal epithelium. Moreover Cyclin D2 dramatically reduced tumor growth and development in ApcMin/+ mice. Importantly Cyclin D2 knockout did not affect proliferation of normal enterocytes and furthermore CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from ApcMin/+ mice. Taken together, these results indicate that Cyclin D-CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling and inhibiting this complex may be an effective chemopreventative strategy in colorectal cancer.