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p16(INK4a) 的 C 端结构域足以诱导细胞周期停滞、生长抑制和 CDK4/6 相互作用,与 HT-1080 纤维肉瘤细胞中的全长蛋白相似。

C-terminal domain of p16(INK4a) is adequate in inducing cell cycle arrest, growth inhibition and CDK4/6 interaction similar to the full length protein in HT-1080 fibrosarcoma cells.

机构信息

Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.

出版信息

J Cell Biochem. 2010 Dec 15;111(6):1598-606. doi: 10.1002/jcb.22892.

Abstract

The tumor suppressor p16(INK4a) has earned widespread attention in cancer studies since its discovery as an inhibitor of cyclin-dependent kinases (CDKs) 4/6. Structurally, it consists of four complete ankyrin repeats, believed to be involved in CDK4 interaction. According to the previous disparities concerning the importance of domains and inactivating mutations in p16, we aimed to search for the domain possessing the functional properties of the full length protein. Upon our in silico screening analyses followed by experimental assessments, we have identified the novel minimum functional domain of p16 to be the C-terminal half including ankyrin repeats III, IV and the C-terminal flanking region accompanied by loops 2 and 3. Transfection of this truncated form into HT-1080 human fibrosarcoma cells, lacking endogenous p16, revealed that it is able to inhibit cell growth and proliferation equivalent to p16(INK4a). The functional analysis showed that this fragment like p16 can interact with CDK4/6, block the entry into S phase of the cell cycle and suppress growth as indicated by colony formation assay. Identification of p16 minimum functional domain can be of benefit to the future peptidomimetic drug design as well as gene transfer for cancer therapy.

摘要

肿瘤抑制因子 p16(INK4a)作为细胞周期蛋白依赖性激酶(CDKs)4/6 的抑制剂,自发现以来在癌症研究中受到广泛关注。在结构上,它由四个完整的锚重复序列组成,据信与 CDK4 相互作用有关。根据先前关于 p16 结构域和失活突变重要性的差异,我们旨在寻找具有全长蛋白功能特性的结构域。经过我们的计算机筛选分析和实验评估,我们已经确定了 p16 的新型最小功能结构域为包括锚重复 III、IV 和 C 端侧翼区域以及环 2 和 3 的 C 端一半。将这种截断形式转染到缺乏内源性 p16 的 HT-1080 人纤维肉瘤细胞中,表明它能够抑制细胞生长和增殖,与 p16(INK4a)相当。功能分析表明,该片段与 p16 一样能够与 CDK4/6 相互作用,阻止细胞周期进入 S 期,并通过集落形成实验抑制生长。鉴定 p16 的最小功能结构域可以有益于未来的肽模拟药物设计以及癌症治疗的基因转移。

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