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Blood. 2010 Apr 29;115(17):3559-69. doi: 10.1182/blood-2009-08-236760. Epub 2010 Feb 25.

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

Author information

1
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey (UMDNJ)--Robert Wood Johnson Medical School, Piscataway, USA.

Abstract

The antiapoptotic Bcl-2 family member Bfl-1 is up-regulated in many human tumors in which nuclear factor-kappaB (NF-kappaB) is implicated and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-kappaB 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.

PMID:
20185581
PMCID:
PMC2867266
DOI:
10.1182/blood-2009-08-236760
[Indexed for MEDLINE]
Free PMC Article

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