文章：

Cdk抑制剂p27在人类癌症中的预后潜力及其与抗癌治疗的相关性

The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy

原文发布日期：2008-04-01

DOI: 10.1038/nrc2347

类型: Review Article

开放获取: 否

要点：

1. p27 (also known as KIP1, and encoded by CDKN1B) is regulated by multiple signal transduction pathways in normal and malignant cells.
2. CDKN1B transcription can be regulated by the FoxO family and genetic defects that reduce CDKN1B transcription can predispose to multiple endocrine neoplasia (MEN)-like phenotypes.
3. CDKN1B 5′UTR mediates its cell cycle-dependent translation and several proteins can bind the CDKN1B IRES to modulate its translation.
4. micro-RNA-mediated inhibition of p27 translation emerges as a novel mechanism that can reduce p27 in some human cancers.
5. p27 proteolysis is initiated by several different mechanisms.
6. Tyrosine (Tyr) phosphorylation of p27 by Abl and Src family kinases reduces p27–CDK2 inhibition and transforms p27 from inhibitor to substrate of cyclin–CDK2 complexes.
7. p27 phosphorylation at Thr157 and Thr198 by members of the AGC kinase family promotes assembly of p27–cyclin D–CDK4/6, but catalytic activation requires tyrosine phosphorylation.
8. Cytoplasmic mislocalization of p27 is activated by AGC family kinases and contributes to RHOA inhibition and increased cell motility in cancers.
9. p27 levels are reduced in the most common and lethal human epithelial cancers and this is associated with poor patient outcome.
10. Restoration of p27 levels and/or nuclear localization may predict response to molecular therapies that target EGFR and IGFR families, MAP2K (also known as MEK), BCR-ABL and SRC.

要点翻译：

1. p27（亦称KIP1，由CDKN1B基因编码）在正常细胞与恶性细胞中受多种信号转导通路调控。
2. CDKN1B转录可受FoxO家族调控，其转录功能减弱的遗传缺陷可能诱发多发性内分泌瘤样表型。
3. CDKN1B的5′非翻译区介导细胞周期依赖性翻译，多种蛋白可通过结合CDKN1B的IRES区域调节其翻译过程。
4. 微小RNA介导的p27翻译抑制已成为某些人类癌症中p27水平下降的新机制。
5. p27的蛋白水解由多种不同机制启动。
6. Abl和Src家族激酶对p27的酪氨酸磷酸化会减弱p27–CDK2抑制作用，并将p27从抑制剂转化为周期蛋白-CDK2复合物的底物。
7. AGC激酶家族成员对p27苏氨酸157/198位点的磷酸化可促进p27-周期蛋白D-CDK4/6复合物组装，但其催化激活需酪氨酸磷酸化参与。
8. AGC家族激酶激活的p27胞质错误定位会抑制RHOA并增强癌细胞运动能力。
9. 在最常见且致死率高的上皮源性人类癌症中，p27水平降低与患者不良预后相关。
10. p27水平及/或核定位的恢复可能预示针对EGFR/IGFR家族、MAP2K（亦称MEK）、BCR-ABL和SRC的分子靶向治疗疗效。

英文摘要：

The cyclin-dependent kinase (Cdk) inhibitor p27 (also known as KIP1) regulates cell proliferation, cell motility and apoptosis. Interestingly, the protein can exert both positive and negative functions on these processes. Diverse post-translational modifications determine the physiological role of p27. Phosphorylation regulates p27 binding to and inhibition of cyclin–Cdk complexes, its localization and its ubiquitin-mediated proteolysis. In cancers, p27 is inactivated through impaired synthesis, accelerated degradation and by mislocalization. Moreover, studies in several tumour types indicate that p27 expression levels have both prognostic and therapeutic implications.

摘要翻译： 

细胞周期蛋白依赖性激酶（Cdk）抑制因子p27（又称KIP1）调控细胞增殖、细胞运动和凋亡。有趣的是，该蛋白在这些过程中既可发挥正向功能，也可发挥负向功能。多种翻译后修饰决定了p27的生理作用。磷酸化调控p27与细胞周期蛋白-Cdk复合物的结合及其抑制活性、亚细胞定位以及泛素介导的蛋白降解。在癌症中，p27通过合成受损、加速降解和错误定位而失活。此外，对多种肿瘤类型的研究表明，p27的表达水平具有预后和治疗意义。

原文链接：

The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy