Cheon Kang Woo, Baek Kwang-Hyun
Graduate School of Life Science and Biotechnology, Cell and Gene Therapy Research Institute, Pochon CHA University, CHA General Hospital, Seoul 135-081, Korea.
Int J Oncol. 2006 May;28(5):1209-15.
p53, one of the most important tumor suppressor proteins, plays an essential role in regulating the cell cycle and apoptosis by sensing the integrity of genome. Therefore, the level of p53 protein is critical for normal cellular homeostasis, and is known to be subtly regulated by ubiquitination and deubiquitination systems. Numerous genetic alterations of p53 have been reported in all types of tumors. In hematopoietic tumors, the mutations of p53 gene are rare compared with solid tumors, which showed more than 50% frequency for p53 mutations. According to this characteristic feature of hematological tumors, the therapeutic strategy for targeting the level of p53 may be valuable in anti-cancer treatment of hematological tumors. Herein, we deal with the post-translational regulation of p53 via its specific ubiquitinating enzymes (Mdm2, Mdmx, COP1, Pirh2, ARF-BP1/Mule, and CHIP) and a deubiquitinating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP). In this article, we review the regulatory mechanism of p53 via ubiquitination and deubiquitination system and suggest the several possible therapeutic strategies of targeting HAUSP, a deubiquitinating enzyme for p53, for treating hematopoietic tumors.
p53是最重要的肿瘤抑制蛋白之一，通过感知基因组的完整性在调节细胞周期和细胞凋亡中发挥重要作用。因此，p53蛋白的水平对于正常细胞内环境稳定至关重要，并且已知其受到泛素化和去泛素化系统的精细调节。在所有类型的肿瘤中均已报道了p53的大量基因改变。在造血系统肿瘤中，与实体瘤相比，p53基因的突变较少，实体瘤中p53突变的频率超过50%。根据血液系统肿瘤的这一特征，靶向p53水平的治疗策略在血液系统肿瘤的抗癌治疗中可能具有重要价值。在此，我们探讨通过其特异性泛素化酶（Mdm2、Mdmx、COP1、Pirh2、ARF-BP1/Mule和CHIP）以及一种去泛素化酶——疱疹病毒相关泛素特异性蛋白酶（HAUSP）对p53进行的翻译后调控。在本文中，我们综述了通过泛素化和去泛素化系统对p53的调控机制，并提出了几种靶向p53去泛素化酶HAUSP治疗造血系统肿瘤的可能治疗策略。
