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.