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 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.

艾贝尔森鼠白血病病毒（A - MuLV）编码v - Abl，这是一种普遍存在的细胞非受体酪氨酸激酶c - Abl的致癌形式。A - MuLV在体内和体外都能特异性地转化鼠B细胞前体。通过添加小分子抑制剂STI - 571抑制v - Abl，会使这些细胞在经历细胞凋亡之前停滞在细胞周期的G1期。我们发现抑制v - Abl活性会导致促凋亡的肿瘤坏死因子家族配体TRAIL（肿瘤坏死因子相关凋亡诱导配体）的转录上调。与BCR - Abl转化的人类细胞类似，转录因子Foxo3a的激活在没有v - Abl抑制的情况下导致TRAIL转录增加以及G1期停滞的诱导，并且这种效应可被组成型活性AKT突变体的表达所抑制。多种途径作用于抑制艾贝尔森细胞内的FoxO3a活性。除了通过AKT家族成员的抑制性磷酸化降低转录因子活性外，我们还发现抑制IKKβ活性会导致FoxO3a的总蛋白水平增加。此外，NF - κB的p65亚基的过表达会导致TRAIL转录增加以及细胞凋亡，而IKKα和β的缺失会降低TRAIL的表达和诱导。我们得出结论，在艾贝尔森细胞中，抑制NF - κB和FoxO3a的活性对于抑制TRAIL转录以及维持转化状态是必需的。