Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies.
Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies.
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DOI：
10.1158/0008-5472.can-18-1235
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发表时间：
2018-10-01
期刊：
影响因子：
11.2
通讯作者：
Keyomarsi K
中科院分区：
文献类型：
--
作者：
Caruso JA;Duong MT;Carey JPW;Hunt KK;Keyomarsi K
细胞周期蛋白E是细胞周期蛋白依赖性激酶2（CDK 2）的调节亚基，在G1/S-检查点启动DNA复制至关重要。细胞周期蛋白E的严格时间控制对于协调细胞周期过程和维持基因组完整性至关重要。在20世纪90年代首次观察到人类肿瘤中细胞周期蛋白E的过表达，并导致在实验模型中鉴定出去调节的细胞周期蛋白E的致癌作用。十年后，在侵袭性肿瘤亚型中观察到低分子量细胞周期蛋白E亚型（LMW-E）。与全长细胞周期蛋白E相比，LMW-E通过增加复合物稳定性和对内源性抑制剂p21 CIP 1和p27 KIP 1的抗性来过度激活CDK 2。LMW-E主要由中性粒细胞弹性蛋白酶介导的蛋白水解切割产生，其消除N-末端细胞周期蛋白E核定位信号并促进细胞周期蛋白E在细胞质中的积累。与全长细胞周期蛋白E相比，LMW-E的异常定位和独特的立体化学显著改变了CDK 2的底物特异性和选择性，增加了实验模型中的致瘤性。细胞质LMW-E可以通过免疫组织化学进行评估，是癌症患者生存不良的预后指标，并可预测对标准治疗的耐药性。这些患者可能受益于针对LMW-E的生物化学改变或其相关脆弱性的治疗方式。
Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (CDK2), is central to the initiation of DNA replication at the G1/S-checkpoint. Tight temporal control of cyclin E is essential to the coordination of cell cycle processes and the maintenance of genome integrity. Overexpression of cyclin E in human tumors was first observed in the 1990s and led to the identification of oncogenic roles for deregulated cyclin E in experimental models. A decade later, low molecular weight cyclin E isoforms (LMW-E) were observed in aggressive tumor subtypes. Compared with full-length cyclin E, LMW-E hyperactivates CDK2 through increased complex stability and resistance to the endogenous inhibitors p21CIP1 and p27KIP1. LMW-E is predominantly generated by neutrophil elastase-mediated proteolytic cleavage, which eliminates the N-terminal cyclin E nuclear localization signal and promotes cyclin E’s accumulation in the cytoplasm. Compared with full-length cyclin E, the aberrant localization and unique stereochemistry of LMW-E dramatically alters the substrate specificity and selectivity of CDK2, increasing tumorigenicity in experimental models. Cytoplasmic LMW-E, which can be assessed by immunohistochemistry, is prognostic of poor survival and predicts resistance to standard therapies in cancer patients. These patients may benefit from therapeutic modalities targeting the altered biochemistry of LMW-E or its associated vulnerabilities.