title: The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the proteasome.
abstract: Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway by the viral Tax oncoprotein plays a pivotal role in clonal expansion of human T-cell leukemia virus type 1 (HTLV-1)-infected cells. As the Forkhead box O (FoxO) tumor suppressors act as downstream effectors of PI3K/Akt, they represent good candidate targets whose dysregulation by Tax might be involved in HTLV-1-mediated activation and transformation of infected cells. In this report, we provide evidence showing that Tax induces a dose-dependent degradation of FoxO4 by the ubiquitin-proteasome pathway. Consistent with that, we demonstrate that Tax expression increases the interaction between FoxO4 and Mdm2 E3 ligase, leading to a strong FoxO4 polyubiquitination. These processes require the phosphorylation of FoxO4 by Akt, since a mutant of FoxO4 with mutations on its three Akt phosphorylation sites appears to be resistant to Tax-mediated degradation and ubiquitination. In addition, we show that Tax expression is associated with degradation and phosphorylation of endogenous FoxO4 in Jurkat T cells. Finally, we demonstrate that Tax represses FoxO4 transcriptional activity. Our study demonstrates that Tax can control FoxO4 protein stability and transcriptional activity and provides new insight into the subversion of cell signaling pathways during HTLV-1 infection.
authors.affiliation: CNRS UMR 5236, Centre d'Études d'Agents Pathogènes et Biotechnologie pour la Santé (CPBS), 1919 Route de Mende, 34 293 Montpellier Cedex 5, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Oteiza
authors.forename: Nadir
authors.initials: N
authors.lastname: Mechti
mesh_terms: D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D016356:Gene Products, tax; D014157:Transcription Factors; C514970:tax protein, Human T-lymphotrophic virus 1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex