Abelson Virus Transformation Prevents TRAIL Expression by Inhibiting FoxO3a and NF-κB

Abstract

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 TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand). 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 IKKβ activity results in an increase in the total protein level of FoxO3a. Furthermore over-expression of the p65 subunit of NF-κB results in an increase in TRAIL transcription and in apoptosis and deletion of IKKα and β diminishes TRAIL expression and induction. We conclude that in Abelson cells, the inhibition of both NF-κB and FoxO3a activity is required for suppression of TRAIL transcription and maintenance of the transformed state.Constitutively active forms of the ubiquitous protein tyrosine kinase c-Abl are associated with oncogenic transformation in both mouse and man. In humans, a chromosomal translocation results in fusion of the Breakage Cluster Region (BCR) and c-Abl loci resulting in the production of a BCR-Abl fusion protein that is present in nearly 95% of chronic myelogenous leukemia (CML) and about 10% of acute lymphocytic leukemia

FoxO3a and disease progression

“…The activation of the transcription factor FoxO3a led to increased TRAIL transcription and induction of G1 arrest in the absence of v-Abl inhibition; this effect could be inhibited by the expression of a constitutively active Akt mutant in BCR-Abl-transformed human cells. Ghaffari et al [49] also demonstrated that cytokine and BCR-Abl suppression of TRAIL transcription is mediated through phosphorylation and inhibition of the FoxO3a transcription factor. This study showed that BCR-Ablinduced inhibition of TRAIL transcription is linked to the tumorigenicity in chronic myeloid leukemia [50] .…”

“…Cell proliferation and apoptosis Perhaps the two most significant cellular processes that are regulated by FoxO transcription factor are the suppression of cell cycle progression and the promotion of apoptosis [46][47][48][49][50] . FoxO3a activation increases cell cycle inhibitor proteins p21 and p27, both of which subsequently suppress G1 to S cell cycle transition [51][52][53][54] .…”

Post-translational modifications of FOXO family proteins

“…In acute myeloid leukemia cells, FOXO3 is in a constitutively inactive state due to its cytoplasmic localization, which is not dependent on the PI3K/Akt or ERK/MAPK pathways, instead, NF-κB, which is a key regulator of cell survival, sustains a constitutively active state (73). IκK-specific inhibition upregulates FOXO3 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (74). It has also been reported that FOXO3a activates IκK/NF-κB pathways though inducing the B-cell CLL/lymphoma 10 protein (BCL10), which is an upstream regulatory factor of IκK/NF-κB (75).…”

HTLV-1 Tax-Mediated Inhibition of FOXO3a Activity Is Critical for the Persistence of Terminally Differentiated CD4+ T Cells

“…We hypothesized that the enhanced cellular survival observed in HTLV-1 infected CD4 + T cells may be associated with the deregulation of FOXO3a signalling, given its important role in regulating cell proliferation and apoptosis in other retroviral infections [14] , [15] , [24] , [29] . We first investigated at 2 days pi the activation status of AKT, one of the upstream kinases responsible for phosphorylation of FOXO3a [23] ( Fig.…”

“…The expression of HIV-1 regulatory molecule Tat in specific T cells and macrophages also induced FOXO3a-mediated apoptosis [24] , [47] . FOXO3a activity also impacts the pathogenesis and the outcome of Abelson murine leukemia virus [29] .…”