文章：

CDC25磷酸酶在癌细胞中的作用？好的目标吗?

CDC25 phosphatases in cancer cells: key players? Good targets?

原文发布日期：2007-07-01

DOI: 10.1038/nrc2169

类型: Review Article

开放获取: 否

要点：

1. Cell division cycle 25 (CDC25) phosphatases are key regulators of the eukaryotic cell cycle. They are required to control cyclin-dependent kinase (CDK) dephosphorylation and activation in a strict spatio-temporal manner.
2. CDC25A, B and C expression and activity is tightly regulated by many mechanisms, including alternative exon splicing, phosphorylation–dephosphorylation cycles, interactions with partners such as 14-3-3 proteins, intracellular localization and cell-cycle controlled degradation.
3. CDC25 phosphatases are key targets of the checkpoint machinery activated in response to DNA damage. They are functionally inactivated or degraded to stop cell-cycle progression. CDC25B activity is required for checkpoint recovery.
4. CDC25A and CDC25B overexpression are frequently found in many cancers, and are often associated with high-grade tumours and poor prognosis.
5. The contribution of CDC25 phosphatases to tumorigenesis might be related to the genetic instability associated with the checkpoint-abrogating effect of their overexpression.
6. Compounds that inhibit CDC25 phosphatase activities are currently being developed. The most potent quinonoid-based compounds identified so far are active on xenografted tumour models.

要点翻译：

1. 细胞分裂周期25（CDC25）磷酸酶是真核细胞周期的关键调控因子。它们以严格的时空方式控制细胞周期蛋白依赖性激酶（CDK）的去磷酸化与激活过程。
2. CDC25A、B和C的表达及活性受到多种机制的精密调控，包括选择性外显子剪接、磷酸化-去磷酸化循环、与14-3-3蛋白等相互作用因子的结合、细胞内定位以及细胞周期调控的降解过程。
3. CDC25磷酸酶是DNA损伤应答机制中激活的检查点系统的关键靶标。它们通过功能失活或降解来阻止细胞周期进程，而检查点的恢复则需要CDC25B的活性参与。
4. CDC25A和CDC25B的过表达常见于多种恶性肿瘤，通常与高级别肿瘤和不良预后密切相关。
5. CDC25磷酸酶对肿瘤发生的促进作用，可能与其过表达所导致的检查点功能丧失引发的遗传不稳定性相关。
6. 目前正在研发抑制CDC25磷酸酶活性的化合物，迄今发现最有效的醌类化合物已在移植瘤模型中显示出抗肿瘤活性。

英文摘要：

Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.

摘要翻译： 

细胞分裂周期25（CDC25）磷酸酶在正常细胞分裂过程中调控细胞周期各阶段之间的关键转换，而在DNA损伤发生时，它们又是确保遗传稳定性的检查点机制的关键靶点。仅基于此，CDC25在大量人类癌症中的过表达也就不足为奇了。然而，鉴于已有大量证据详述了CDC25活性受到严格而复杂的调控，其在部分癌症中的过表达意义及其与不良预后的关联仍难以评估。我们将重点探讨CDC25磷酸酶在正常与异常细胞增殖中的作用，对目前关于癌症中CDC25过表达的数据进行批判性评估，并讨论当前及未来在癌症治疗中靶向CDC25活性的治疗策略。

原文链接：

CDC25 phosphatases in cancer cells: key players? Good targets?