Abelson virus transformation prevents TRAIL expression by inhibiting FoxO3a and NF-kappaB.
The Abelson Murine Leukemia Virus (A-MuLV) encodes v-Abl, an oncogenic form of the ubiquitous cellular non-receptor tyrosine kinase, c-Abl. A-MuLV specifically transforms murine B cell precursors both in vivo and in vitro. Inhibition of v-Abl by addition of the small molecule inhibitor STI-571 causes these cells to arrest in the G1 phase of the cell cycle prior to undergoing apoptosis. We found that inhibition of v-Abl activity results in upregulation of transcription of the pro-apoptotic TNF-family ligand tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL). Similarly to BCR-Abl-transformed human cells, activation of the transcription factor Foxo3a led to increased TRAIL transcription and induction of a G1 arrest in the absence of v-Abl inhibition, and this effect could be inhibited by the expression of a constitutively active AKT mutant. Multiple pathways act to inhibit FoxO3a activity within Abelson cells. In addition to diminishing transcription factor activity via inhibitory phosphorylation by AKT family members, we found that inhibition of IKKbeta activity results in an increase in the total protein level of FoxO3a. Furthermore overexpression of the p65 subunit of NF-kappaB results in an increase in TRAIL transcription and in apoptosis and deletion of IKKalpha and beta diminishes TRAIL expression and induction. We conclude that in Abelson cells, the inhibition of both NF-kappaB and FoxO3a activity is required for suppression of TRAIL transcription and maintenance of the transformed state.
Wilson
Mary K
MK
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
McWhirter
Sarah M
SM
Amin
Rupesh H
RH
Huang
Dan
D
Schlissel
Mark S
MS
D000011:Abelson murine leukemia virus / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D001549:Benzamides; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase; D054884:Host-Pathogen Interactions; D051550:I-kappa B Kinase / Q000378:metabolism; D000068877:Imatinib Mesylate; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D001549:Benzamides; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016328:NF-kappa B; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D000068877:Imatinib Mesylate; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase