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• Qi, C
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Int. J. Mol. Sci. 2012, 13(5), 6204-6219; doi:10.3390/ijms13056204

Article

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

Chen-Feng Qi ^1,* , Yong-Soo Kim ¹ , Shao Xiang ^1,2 , Ziedulla Abdullaev ¹ , Ted A. Torrey ³ , Siegfried Janz ⁴ , Alexander L. Kovalchuk ¹ , Jiafang Sun ¹ , Delin Chen ⁵ , William C. Cho ⁶ , Wei Gu ⁵  and Herbert C. Morse III ^1,*

¹ Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA ² Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA ³ Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA ⁴ Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA ⁵ Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA ⁶ Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China

* Authors to whom correspondence should be addressed.

Received: 22 March 2012; in revised form: 24 April 2012 / Accepted: 9 May 2012 / Published: 21 May 2012

(This article belongs to the Special Issue Advances in Molecular Oncology)

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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.

Keywords: ARF-BP1; B-cell lymphoma; p53; MYC; CTCF; ARF

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