Distinct proliferative and transcriptional effects of the D-type cyclins in vivo
Distinct proliferative and transcriptional effects of the D-type cyclins in vivo
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DOI：
10.4161/cc.7.14.6274
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发表时间：
2008-07-15
期刊：
影响因子：
4.3
通讯作者：
Albrecht, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Mullany, Lisa K.;White, Peter;Albrecht, Jeffrey H.
D型细胞周期蛋白（D1，D2和D3）是细胞周期机制的组成部分，并控制响应细胞外信号通过G（1）期的进展。虽然这些蛋白质是高度同源和保守的进化，它们包含不同的结构基序，并在不同的细胞类型的差异调节。细胞周期蛋白D1似乎在许多不同类型的癌症中发挥作用，而细胞周期蛋白D2和D3与恶性肿瘤的相关性较低。在这项研究中，我们在肝细胞中瞬时表达细胞周期蛋白D1，D2或D3，并分析了各自调控的转录网络。所有三种D-型细胞周期蛋白促进肝细胞增殖和显着的肝脏生长，虽然细胞周期蛋白D3刺激的DNA合成比D1或D2。因此，三种D型细胞周期蛋白类似地激活与细胞分裂相关的基因。细胞周期蛋白D1调节参与碳水化合物、脂质、氨基酸和其他底物代谢的转录途径，而细胞周期蛋白D2不调节这些途径，尽管对增殖具有同等作用。比较70%部分肝切除术和细胞周期蛋白D1转导后的转录谱发现了非常显著的重叠，表明细胞周期蛋白D1可能调节再生肝脏中的多种细胞过程。总之，这些研究提供了第一个比较分析的转录网络调节的D型细胞周期蛋白，并提供洞察这些关键的细胞周期蛋白的新功能。对细胞周期蛋白D1独特靶点的进一步研究将进一步深入了解其在增殖、生长和癌症中的重要作用。
The D-type cyclins (D1, D2 and D3) are components of the cell cycle machinery and govern progression through G(1) phase in response to extracellular signals. Although these proteins are highly homologous and conserved in evolution, they contain distinct structural motifs and are differentially regulated in various cell types. Cyclin D1 appears to play a role in many different types of cancer, whereas cyclins D2 and D3 are less frequently associated with malignancy. In this study, we transiently expressed cyclin D1, D2 or D3 in hepatocytes and analyzed transcriptional networks regulated by each. All three D-type cyclins promoted robust hepatocyte proliferation and marked liver growth, although cyclin D3 stimulated less DNA synthesis than D1 or D2. Accordingly, the three D-type cyclins similarly activated genes associated with cell division. Cyclin D1 regulated transcriptional pathways involved in the metabolism of carbohydrates, lipids, amino acids, and other substrates, whereas cyclin D2 did not regulate these pathways despite having an equivalent effect on proliferation. Comparison of transcriptional profiles following 70% partial hepatectomy and cyclin D1 transduction revealed a highly significant overlap, suggesting that cyclin D1 may regulate diverse cellular processes in the regenerating liver. In summary, these studies provide the first comparative analysis of the transcriptional networks regulated by the D-type cyclins and provide insight into novel functions of these key cell cycle proteins. Further study of the unique targets of cyclin D1 should provide further insight into its prominent role in proliferation, growth and cancer.