Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms

International Journal of Molecular Sciences

Chen-Feng Qi⁵  Yong-Soo Kim⁵  Shao Xiang⁵  Ziedulla Abdullaev⁵  Ted A. Torrey⁴  Siegfried Janz¹  Alexander L. Kovalchuk⁵  Jiafang Sun⁵  Delin Chen²  William C. Cho³  Wei Gu² 

[1] Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; E-Mail:;Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; E-Mails:;Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China; E-Mail:;Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; E-Mail:;Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA; E-Mails:

关键词: ARF-BP1;    B-cell lymphoma;    p53;    MYC;    CTCF;    ARF;   

DOI  :  10.3390/ijms13056204

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.