Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma.
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.
Fan
Gaofeng
G
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey (UMDNJ)--Robert Wood Johnson Medical School, Piscataway, USA.
Simmons
Matthew J
MJ
Ge
Sheng
S
Dutta-Simmons
Jui
J
Kucharczak
Jérôme
J
Ron
Yacov
Y
Weissmann
David
D
Chen
Chiann-Chyi
CC
Mukherjee
Chandreyee
C
White
Eileen
E
Gélinas
Céline
C
D000818:Animals; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C096816:BCL2-related protein A1; D051034:Inhibitor of Apoptosis Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; C085377:MATK protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex