How the DNA damage response determines the fate of HTLV-1 Tax-expressing cells.

National Fund for Scientific Research, Gembloux Agro-Bio Tech and Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liège, Belgium.
Retrovirology (Impact Factor: 5.66). 01/2012; 9:2. DOI: 10.1186/1742-4690-9-2
Source: PubMed

ABSTRACT How the Human T lymphotropic virus type 1 (HTLV-1) Tax protein stimulates proliferation while triggering cell cycle arrest and senescence remains puzzling. There is also a debate about the ability of Tax to activate or inhibit the DNA damage response. Here, we comment on these different activities and propose a conceptual rationale for the apparently conflicting observations.

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    ABSTRACT: Attenuation of p53 activity appears to be a major step in Human T-lymphotropic virus type 1 (HTLV-1) Tax transformation. However, p53 genomic mutations are late and rather infrequent events in HTLV-1 induced Adult T cell leukemia (ATL). The paper by Zane et al. shows that a mediator of p53 activity, Wild-type p53-induced phosphatase 1 (Wip1), contributes to Tax-induced oncogenesis in a mouse model. Wip1 may therefore be a novel target for therapeutic approaches.
    Retrovirology 12/2012; 9(1):115. · 5.66 Impact Factor
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    ABSTRACT: Autophagy, a general homeostatic process for degradation of cytosolic proteins or organelles, has been reported to modulate the replication of many viruses. The role of autophagy in Human T-cell Leukemia Virus type 1 (HTLV-1) replication has, however, been uncharacterized. Here, we report that HTLV-1 infection increases the accumulation of autophagosomes and that this accumulation increases HTLV-1 production. We found that the HTLV-1 Tax protein increases cellular autophagosome accumulation by acting to block the fusion of autophagosomes to lysosomes, preventing the degradation of the former by the latter. Interestingly, the inhibition of cellular autophagosome-lysosome fusion using Bafilomycin A increased the stability of the Tax protein, suggesting that cellular degradation of Tax occurs in part through autophagy. Our current findings indicate that by interrupting the cell's autophagic process, Tax exerts a positive-feedback on its own stability.
    Journal of Virology 11/2012; · 5.08 Impact Factor
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    ABSTRACT: BACKGROUND: Retroviruses HTLV-1 and HTLV-2 have homologous genomic structures but differ significantly in pathogenicity. HTLV-1 is associated with Adult T cell Leukemia (ATL), whereas infection by HTLV-2 has no association with neoplasia. Transformation of T lymphocytes by HTLV-1 is linked to the capacity of its oncoprotein Tax-1 to alter cell survival and cell cycle control mechanisms. Among these functions, Tax-1-mediated activation of cellular gene expression via the NF-kappaB pathway depends on Tax-1 post-translational modifications by ubiquitination and sumoylation. The Tax-2 protein of HTLV-2B (Tax-2B) is also modified by ubiquitination and sumoylation and activates the NF-kappaB pathway to a level similar to that of Tax-1. The present study aims to understand whether ubiquitination and sumoylation modifications are involved in Tax-2B-mediated activation of the NF-kappaB pathway. RESULTS: The comparison of Tax-1 and Tax-2B lysine to arginine substitution mutants revealed conserved patterns and levels of ubiquitination with notable difference in the lysine usage for sumoylation. Neither Tax-1 nor Tax-2B ubiquitination and sumoylation deficient mutants could activate the NF-kappaB pathway and fusion of ubiquitin or SUMO-1 to the C-terminus of the ubiquitination and sumoylation deficient Tax-2B mutant strikingly restored transcriptional activity. In addition, ubiquitinated forms of Tax-2B colocalized with RelA and IKKgamma in prominent cytoplasmic structures associated with the Golgi apparatus, whereas colocalization of Tax-2B with the RelA subunit of NF-kappaB and the transcriptional coactivator p300 in punctate nuclear structures was dependent on Tax-2B sumoylation, as previously observed for Tax-1. CONCLUSIONS: Both Tax-1 and Tax-2 activate the NF-kappaB pathway via similar mechanisms involving ubiquitination and sumoylation. Therefore, the different transforming potential of HTLV-1 and HTLV-2 is unlikely to be related to different modes of activation of the canonical NF-kappaB pathway.
    Retrovirology 12/2012; 9(1):102. · 5.66 Impact Factor


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