文章：

14-3-3与癌症的联系

The 14-3-3 cancer connection

原文发布日期：2003-12-01

DOI: 10.1038/nrc1230

类型: Review Article

开放获取: 否

要点：

1. Processes that are relevant to cancer biology and that are regulated by 14-3-3 protein interactions include cell-cycle progression, apoptosis and mitogenic signalling.
2. 14-3-3 proteins bind to protein ligands that have been phosphorylated on serine/threonine residues in a consensus binding motif. There are, however, a few proteins that associate with 14-3-3s independently of this motif.
3. 14-3-3 proteins regulate other proteins by cytoplasmic sequestration, occupation of interaction domains and export or import sequences, prevention of degradation, activation/repression of enzymatic activity and transactivation, and facilitation of protein modifications. These effects are caused by 14-3-3-mediated conformational changes or steric hindrance.
4. 14-3-3 proteins form dimers that provide two binding sites for phosphoserine motifs in ligand proteins. They can therefore function as adaptor proteins, bringing two proteins that would not otherwise associate into close proximity. In addition, ligands with two 14-3-3-binding motifs might be bound with higher affinity by one 14-3-3 dimer.
5. In humans, seven expressed 14-3-3 isoforms have been identified, one of which — 14-3-3σ — is induced by DNA damage and is required for a stable G2 cell-cycle arrest in epithelial cells. The 14-3-3σ gene is directly regulated by p53; furthermore, 14-3-3σ is silenced by CpG methylation in a large proportion of carcinomas, which could be used for diagnosis.
6. 14-3-3σ expression is restricted to epithelial cells and increases during epithelial differentiation. Inactivation of 14-3-3σ leads to immortalization of primary keratinocytes and prevents exit from the stem-cell compartment, indicating that this gene has tumour-suppressive properties.
7. Loss of 14-3-3σ expression sensitizes tumour cells to treatment with conventional cytostatic drugs. Modulation of 14-3-3σ activity might therefore be an attractive therapeutic approach.

要点翻译：

1. 与癌症生物学相关且受14-3-3蛋白相互作用调控的过程包括细胞周期进程、细胞凋亡及有丝分裂信号传导。
2. 14-3-3蛋白可与丝氨酸/苏氨酸残基共识结合基序中被磷酸化的蛋白配体结合，但亦有少数蛋白不依赖该基序即可与14-3-3结合。
3. 14-3-3蛋白通过以下机制调控其他蛋白：胞质隔离、占据相互作用结构域、输出或输入序列、阻止降解、激活/抑制酶活性与反式激活，以及促进蛋白修饰。这些效应由14-3-3介导的构象变化或空间位阻引起。
4. 14-3-3蛋白形成二聚体，为配体蛋白中的磷酸丝氨酸基序提供两个结合位点。因此它们可作为衔接蛋白，使原本不相关的两个蛋白相互靠近。此外，具有两个14-3-3结合基序的配体可能与一个14-3-3二聚体以更高亲和力结合。
5. 人类已鉴定出七种表达的14-3-3亚型，其中14-3-3σ由DNA损伤诱导，是上皮细胞稳定G2期细胞周期阻滞所必需的。14-3-3σ基因直接受p53调控；此外，该基因在大部分癌组织中被CpG甲基化沉默，这一特性可用于诊断。
6. 14-3-3σ表达仅限于上皮细胞，并随上皮分化进程增强。其失活会导致原代角质形成细胞永生化，并阻止细胞退出干细胞区室，表明该基因具有肿瘤抑制特性。
7. 14-3-3σ表达缺失使肿瘤细胞对常规细胞抑制药物更敏感。因此调控14-3-3σ活性可能成为具有吸引力的治疗策略。

英文摘要：

14-3-3 proteins regulate many cellular processes that are important in cancer biology, such as apoptosis and cell-cycle checkpoints. There are seven human 14-3-3 genes and one of these, 14-3-3σ, has been directly implicated in the aetiology of human cancer. Loss of 14-3-3σ expression sensitizes cancer cells to conventional anticancer agents, so its inhibition could be exploited for therapeutic purposes. Interference with 14-3-3 function as a therapeutic approach is being evaluated at present and, in the case of UCN-01, is under clinical investigation.

摘要翻译： 

14-3-3蛋白调控许多对癌症生物学至关重要的细胞过程，如凋亡和细胞周期检查点。人类共有七个14-3-3基因，其中14-3-3σ已被直接证实与人类癌症的病因相关。14-3-3σ表达的缺失会使癌细胞对传统抗癌药物更加敏感，因此抑制其功能可被用于治疗目的。目前，干扰14-3-3功能的治疗策略正在被评估，其中UCN-01已进入临床研究阶段。

原文链接：

The 14-3-3 cancer connection