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Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms
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
Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA
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
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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Qi, C.-F.; Kim, Y.-S.; Xiang, S.; Abdullaev, Z.; Torrey, T.A.; Janz, S.; Kovalchuk, A.L.; Sun, J.; Chen, D.; Cho, W.C.; Gu, W.; Morse III, H.C. Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms. Int. J. Mol. Sci. 2012, 13, 6204-6219.
Qi C-F, Kim Y-S, Xiang S, Abdullaev Z, Torrey TA, Janz S, Kovalchuk AL, Sun J, Chen D, Cho WC, Gu W, Morse III HC. Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms. International Journal of Molecular Sciences. 2012; 13(5):6204-6219.
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. 2012. "Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms." Int. J. Mol. Sci. 13, no. 5: 6204-6219.