Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mod Pathol. 2010 Mar;23(3):381-91. doi: 10.1038/modpathol.2009.170. Epub 2010 Jan 8.
In mouse models and cell lines, murine double minute 2 (MDM2) and MDM4 have been shown to synergistically promote proteasome-mediated degradation of p21 and p53. MDM4 also inhibits p53-mediated transcriptional activation of p21. p53 expression results in increased p21 expression, a negative cell-cycle regulatory protein and an inhibitor of cyclin D1. As mantle cell lymphoma is characterized by cyclin D1 overexpression, we assessed for human homolog of MDM4 (HDM4) expression and its effect on p21 in mantle cell lymphoma. Using immunohistochemical methods, in reactive lymph nodes (n=19) germinal center cells strongly expressed HDM4 in the nucleus and the cytoplasm, but mantle zone B-cells were only dimly positive. In mantle cell lymphoma tumors, aberrant HDM4 nuclear expression was observed in 18 of 19 (95%) cases. In contrast, HDM4 in other B-cell non-Hodgkin lymphoma types retained its normal pattern of expression. To further characterize the differential upregulation of HDM4 in mantle cell lymphoma, HDM4 was assessed by quantitative real-time polymerase chain reaction in four mantle cell lymphoma cell lines (Granta 519, Z-138, SP-53, and Mino) and six mantle cell lymphoma tumors. Both the splicing variant HDM4-S, containing only the p53-binding domain, and full length HDM4 were increased compared with normal CD19+ B-cells (P<0.05). Using small interfering RNA to inhibit HDM4 in the SP53 and Mino cell lines showed increased p21 and active caspase-3, the latter indicating increased apoptosis. Our results show that HDM4 is overexpressed in mantle cell lymphoma and, at least in part, exerts its effect by suppressing p21 expression, thereby enhancing cell-cycle progression. Inhibition of HDM4 may serve as a potential approach in the design of therapy for patients with mantle cell lymphoma.
在小鼠模型和细胞系中，已经证实鼠双微体 2（MDM2）和 MDM4 协同促进蛋白酶体介导的 p21 和 p53 的降解。MDM4 还抑制 p53 介导的 p21 的转录激活。p53 的表达导致 p21 表达增加，p21 是一种负性细胞周期调节蛋白，也是细胞周期蛋白 D1 的抑制剂。由于套细胞淋巴瘤的特征是细胞周期蛋白 D1 过度表达，我们评估了人类 MDM4 同源物（HDM4）的表达及其对套细胞淋巴瘤中 p21 的影响。使用免疫组织化学方法，在反应性淋巴结（n=19）中，生发中心细胞在核和细胞质中强烈表达 HDM4，但套区 B 细胞仅呈微弱阳性。在套细胞淋巴瘤肿瘤中，19 例（95%）中有 18 例观察到异常的 HDM4 核表达。相比之下，其他 B 细胞非霍奇金淋巴瘤类型中的 HDM4 保留了其正常的表达模式。为了进一步描述 HDM4 在套细胞淋巴瘤中的差异上调，我们通过定量实时聚合酶链反应在 4 种套细胞淋巴瘤细胞系（Granta 519、Z-138、SP-53 和 Mino）和 6 种套细胞淋巴瘤肿瘤中评估了 HDM4。与正常 CD19+B 细胞相比，剪接变异体 HDM4-S（仅包含 p53 结合域）和全长 HDM4 均增加（P<0.05）。使用小干扰 RNA 抑制 SP53 和 Mino 细胞系中的 HDM4 显示 p21 和活性 caspase-3 增加，后者表明细胞凋亡增加。我们的结果表明，HDM4 在套细胞淋巴瘤中过度表达，至少部分通过抑制 p21 表达来发挥作用，从而增强细胞周期进程。抑制 HDM4 可能成为设计套细胞淋巴瘤患者治疗方案的一种潜在方法。
