title: Characterization of ARF-BP1/HUWE1 interactions with CTCF, MYC, ARF and p53 in MYC-driven B cell neoplasms.
abstract: 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.
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Chen-Feng
authors: CF
authors: Qi
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Yong-Soo
authors: YS
authors: Kim
authors: 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.
authors: Shao
authors: S
authors: Xiang
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Ziedulla
authors: Z
authors: Abdullaev
authors: Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Ted A
authors: TA
authors: Torrey
authors: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors: Siegfried
authors: S
authors: Janz
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Alexander L
authors: AL
authors: Kovalchuk
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Jiafang
authors: J
authors: Sun
authors: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors: Delin
authors: D
authors: Chen
authors: Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
authors: William C
authors: 0000-0003-4174-4586
authors: WC
authors: Cho
authors: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
authors: Wei
authors: W
authors: Gu
authors: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors: Herbert C
authors: HC
authors: Morse Iii
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C502830:HUWE1 protein, human; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases