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Characterization of ARF-BP1/HUWE1 interactions with CTCF, MYC, ARF and p53 in MYC-driven B cell neoplasms. Int J Mol Sci 2012;13(5):6204-19

Date

07/04/2012

Pubmed ID

22754359

Pubmed Central ID

PMC3382761

DOI

10.3390/ijms13056204

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.

Author List

Qi CF, Kim YS, Xiang S, Abdullaev Z, Torrey TA, Janz S, Kovalchuk AL, Sun J, Chen D, Cho WC, Gu W, Morse HC 3rd

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
CCCTC-Binding Factor
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Lymphoma, B-Cell
Mice
Neoplasms, Experimental
Proto-Oncogene Proteins c-myc
Repressor Proteins
Signal Transduction
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc