E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis Journal Article

   


Authors: Wolyniec, K.; Shortt, J.; de Stanchina, E.; Levav-Cohen, Y.; Alsheich-Bartok, O.; Louria-Hayon, I.; Corneille, V.; Kumar, B.; Woods, S. J.; Opat, S.; Johnstone, R. W.; Scott, C. L.; Segal, D.; Pandolfi, P. P.; Fox, S.; Strasser, A.; Jiang, Y. H.; Lowe, S. W.; Haupt, S.; Haupt, Y.
Article Title: E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis
Abstract: Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in ∼ 60% of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma. © 2012 by The American Society of Hematology.
Keywords: controlled study; human tissue; protein expression; unclassified drug; nonhuman; mouse; animal tissue; protein p16; ubiquitin protein ligase; cancer inhibition; b cell lymphoma; histone h3; myc protein; down regulation; protein p21; cell aging; burkitt lymphoma; promyelocytic leukemia protein; e6ap ubiquitin ligase
Journal Title: Blood
Volume: 120
Issue: 4
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2012-07-26
Start Page: 822
End Page: 832
Language: English
DOI: 10.1182/blood-2011-10-387647
PROVIDER: scopus
PUBMED: 22689861
PMCID: PMC3709628
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84864495265&partnerID=40&md5=2eb1c5fe681ac62149fb95bc0f3b9259
Notes: --- - "Export Date: 4 September 2012" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Elisa De Stanchina
    347 De Stanchina
  2. Scott W Lowe
    249 Lowe
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