这些细胞的潜在的染色体不稳定性有助于cyclin E失调节的致肿瘤作用。以上这几种机制可能同时存在并协同作用,当cyclin E的代谢机制受损时,cyclin E的持续失调节导致CIN。
3 Cyclin E失调节新的研究方向
除了SCFCdc4在cyclin E turnover中有重要作用,其他的此类合成酶也被确认,包括c-Myc与信号域槽蛋白(signaling domains of Notch proteins),都与肿瘤发生有关。下一步工作就是确定在hCdc4/Fbw7突变所介导的肿瘤发生过程中哪一种是关键的底物。另外, SCFCdc4的作用靶物质还不甚明了,明确与SCFCdc4有关的所有生物学底物可以帮助我们更全面的理解SCFCdc4在肿瘤发生中的作用。近期的研究表明hCdc4/Fbw7是一个非单一有效的肿瘤抑制因子,由此提出了几点论题:(1)明确SCFCdc4的作用的靶物质是今后研究的关键;(2)由于hCdc4/Fbw7功能的缺失引起cyclin E的失调节导致肿瘤发生,利用hCdc4/Fbw7作为分子标记,可以做肿瘤的早期诊断;(3)对于肿瘤的预防和治疗,利用hCdc4/Fbw7的肿瘤抑制因子特性可能可以开发特异性的提高SCFCdc4活性的药物。使用药物提高SCFCdc4的活性可能在加强cyclin E turnover方面早期预防肿瘤。
【参考文献】
1 Tetsu O ,Mccormick F . Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell,2003,3: 233~245.
2 Berthet C, Aleem E, Coppola V, et al. Cdk2 knockout mice are viable. Curr Biol, 2003,13: 1775~1785.
3 Ortega S, Prieto I, Odajima J, et al. Cyclin-dependent kinase-2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet, 2003,35: 25~31.
4 Geng Y, Yu Q, Sicinska E, et al. Cyclin E ablation in the mouse. Cell,2003,114: 431~443.
5 Coverley D, Laman H, Laskey RA ,et al. Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat Cell Biol,2002,(4): 523~528.
6 Hwang HC, Clurman BE. Cyclin E in normal and neoplastic cell cycles. Oncogene April,2005, 24(17): 2776~2786.
7 Spruck CH, Won KA, Reed SI. Deregulated cyclin E induces chromosome instability. Nature,1999,401:297~300.
8 Winston JT, Claire C, Harper JW.Culprits in the degradation of cyclin E apprehended. GENES & DEVELOPMENT,1999,13:2751~2757.
9 Rory DO , Runjan C. Cyclin E in human cancers. The FASEB Journal, 1999,13:773~780.
10 Spruck H, Heimo S, Olle S, et al. hCDC4 Gene Mutations in Endometrial Cancer. Cancer Research August,2002,62: 4535~4539.
11 Koepp DM, Schaefer LK, Ye X, et al. Phosphorylation-dependent ubiquitination of cyclin E by
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