Qi Chen-Feng, Kim Yong-Soo, Xiang Shao, Abdullaev Ziedulla, Torrey Ted A, Janz Siegfried, Kovalchuk Alexander L, Sun Jiafang, Chen Delin, Cho William C, Gu Wei, Morse Iii Herbert C
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Int J Mol Sci. 2012;13(5):6204-6219. doi: 10.3390/ijms13056204. Epub 2012 May 21.
Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is involved in the pathogenesis of MYC-driven B cell lymphomas. ARF-BP1 was expressed at high levels in cell lines from lymphomas with either wild type or mutated p53 but not in ARF-deficient cells. Downregulation of ARF-BP1 resulted in elevated steady state levels of p53, growth arrest and apoptosis. Co-immunoprecipitation studies identified a multiprotein complex comprised of ARF-BP1, ARF, p53, MYC and the multifunctional DNA-binding factor, CTCF, which is involved in the transcriptional regulation of MYC, p53 and ARF. ARF-BP1 bound and ubiquitylated CTCF leading to its proteasomal degradation. ARF-BP1 and CTCF thus appear to be key cofactors linking the MYC proliferative and p53-ARF apoptotic pathways. In addition, ARF-BP1 could be a therapeutic target for MYC-driven B lineage neoplasms, even if p53 is inactive, with inhibition reducing the transcriptional activity of MYC for its target genes and stabilizing the apoptosis-promoting activities of p53.
MYC的转录激活是许多B细胞系肿瘤的一个标志。MYC提供组成性增殖信号，但也可启动ARF依赖的p53激活和凋亡。由HUWE1编码的E3泛素连接酶ARF-BP1调节MYC和ARF-p53信号通路的活性，促使我们确定它是否参与MYC驱动的B细胞淋巴瘤的发病机制。ARF-BP1在野生型或p53突变的淋巴瘤细胞系中高表达，但在ARF缺陷细胞中不表达。ARF-BP1的下调导致p53稳态水平升高、生长停滞和凋亡。免疫共沉淀研究鉴定出一个由ARF-BP1、ARF、p53、MYC和多功能DNA结合因子CTCF组成的多蛋白复合物，CTCF参与MYC、p53和ARF的转录调控。ARF-BP1结合并泛素化CTCF，导致其经蛋白酶体降解。因此，ARF-BP1和CTCF似乎是连接MYC增殖和p53-ARF凋亡通路的关键辅因子。此外，即使p53无活性，ARF-BP1也可能是MYC驱动的B系肿瘤的治疗靶点，抑制ARF-BP1可降低MYC对其靶基因的转录活性，并稳定p53的促凋亡活性。
