文献简介

出版社:Human Pathology

作  者:Vasiliki Leventaki , Elias Drakos, Maria Karanikou, Konstantina Psatha , Pei Lin Ellen Schlette , Aris Eliopoulos

编  号:

关键字:JNK; c-JUN; p21; Hodgkin lymphoma; Non-Hodgkin lymphoma; Cell cycle

年  份:2014   点击量:742

文献摘要


Abstract:
c-JUN N-terminal Kinase (JNK) is activated/phosphorylated by upstream MAPK kinases (MKK), and, in turn, phosphorylates and activates its major substrate c-JUN, a member of the activator protein-1 (AP-1) transcription factors. c-JUN is overexpressed and activated in Hodgkin and Reed Sternberg cells (HRS) of classical Hodgkin lymphoma (cHL), however, the mechanism of its activation remains unknown. JNK activation was immunohistochemically assessed in 60 cases of HL and in a control group of 151 B-cell non-Hodgkin lymphomas. The biologic effects of JNK activation in cultured HRS cells were investigated using colony formation, cell growth and viability assays and cell cycle analysis by flow cytometry. Western blotting was used to assess protein levels. p-JNK was expressed in 90% of HL, 83% of Burkitt lymphomas, 28% of mantle cell lymphomas, 23% of diffuse large B-cell lymphomas, 19% of follicular lymphomas, and 18% of extranodal marginal zone lymphomas of MALT type. None of the 48 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma and 18 cases of plasma cell myeloma showed JNK phosphorylation (P<001, Kruskall-Wallis test). Pharmacological inhibition of JNK activity in cultured HRS cells resulted in a significant decrease of cell growth, which was associated with cell cycle arrest at the G2/M phase. The cell cycle effects were linked to deactivation of c-JUN and upregulation of its known target, the cyclin-dependent kinase inhibitor p21. JNK is highly activated in HRS cells, and may contribute to uncontrolled cell cycle progression and proliferation of tumor cells in cHL.
摘要:
c-JUN氨基末端激酶(JNK)通过上游MAPK激酶(MKK)激活/磷酸化,并且反过来,使它的主要底物c- JUN,激活蛋白-1(AP-1)转录因子的成员之一磷酸化和激活。c- JUN在经典型霍奇金淋巴瘤(cHL)的霍奇金和里德-斯腾伯格细胞(HRS)中过表达与被激活,但其激活机制尚不清楚。在60例HL和在151的B-细胞非霍奇金淋巴瘤的对照组中,我们对JNK的活化进行免疫组织化学评估。在培养的HRS细胞中,我们通过菌落形成、细胞生长和可行性试验对JNK活化的生物效应进行研究,并采用流式细胞仪对细胞周期进行分析。我们用Western印迹法来评估蛋白质水平。在90%的HL、83%的伯基特淋巴瘤、28%的套细胞淋巴瘤、23%的弥漫性大B细胞淋巴瘤、19%的滤泡性淋巴瘤和18%的MALT型的结外边缘区淋巴瘤中磷酸化JNK中得到了表达。48例慢性淋巴细胞白血病/小淋巴细胞性淋巴瘤和18例浆细胞骨髓瘤中没有一例表现为JNK磷酸化(P<001,Kruskall -Wallis检验)。在培养的HRS细胞中通过药物抑制JNK活性会导致细胞生长显著减少,这与G2/M期细胞周期阻滞有关。细胞周期的影响与c- JUN的失活以及它的已知靶目标-细胞周期蛋白依赖性激酶抑制剂p21的上调有联系。在HRS细胞中JNK高度活化,并且可能促进cHL中不受控制的细胞周期进程提高和肿瘤细胞的扩散。