Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma

Gaofeng Fan 1, 2 Matthew J. Simmons 1, 2 Sheng Ge 1 Jui Dutta-Simmons 1, 2 Jérôme Kucharczak 1 Yacov Ron 3 David Weissmann 4 Chiann-Chyi Chen 3 Chandreyee Mukherjee 1 Eileen White 1, 5, 6 Céline Gélinas 1, 6, 7
1 Center for Advanced Biotechnology and Medicine
2 Graduate Program in Biochemistry and Molecular Biology
3 Department of Molecular Genetics, Microbiology and Immunology
4 Robert Wood Johnson University Hospital
5 Department of Molecular Biology and Biochemistry
6 Cancer Institute of New Jersey
7 Department of Biochemistry
Abstract : The antiapoptotic Bcl-2 family member Bfl-1 is up-regulated in many human tumors in which nuclear factor-κB (NF-κB) is implicated and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-κB induces transcription of bfl-1 and that the Bfl-1 protein is also regulated by ubiquitin-mediated proteasomal degradation. However, the role that dysregulation of Bfl-1 turnover plays in cancer is not known. Here we show that ubiquitination-resistant mutants of Bfl-1 display increased stability and greatly accelerated tumor formation in a mouse model of leukemia/lymphoma. We also show that tyrosine kinase Lck is up-regulated and activated in these tumors and leads to activation of the IkappaB kinase, Akt, and extracellular signal-regulated protein kinase signaling pathways, which are key mediators in cancer. Coexpression of Bfl-1 and constitutively active Lck promoted tumor formation, whereas Lck knockdown in tumor-derived cells suppressed leukemia/lymphomagenesis. These data demonstrate that ubiquitination is a critical tumor suppression mechanism regulating Bfl-1 function and suggest that mutations in bfl-1 or in the signaling pathways that control its ubiquitination may predispose one to cancer. Furthermore, because bfl-1 is up-regulated in many human hematopoietic tumors, this finding suggests that strategies to promote Bfl-1 ubiquitination may improve therapy.
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Journal articles
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https://hal-ens-lyon.archives-ouvertes.fr/ensl-00815695
Contributor : Agnès Ganivet <>
Submitted on : Friday, April 19, 2013 - 11:14:56 AM
Last modification on : Wednesday, November 20, 2019 - 7:59:32 AM

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  • HAL Id : ensl-00815695, version 1
  • DOI : 10.1182

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Gaofeng Fan, Matthew J. Simmons, Sheng Ge, Jui Dutta-Simmons, Jérôme Kucharczak, et al.. Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma. Blood, American Society of Hematology, 2010, 115 (17), pp.3559-3569. ⟨10.1182⟩. ⟨ensl-00815695⟩

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