Acetylation at lysine 346 controls the transforming activity of the HTLV-1 Tax oncoprotein in the Rat-1 fibroblast model

Retrovirology

Françoise Bex¹  Pierre P Roger³  Luc Willems²  Katia Coulonval³  Anne-Sophie Rinaldi¹  Mathieu Boxus²  Carla Sampaio³  Julie Lodewick¹ 

[1] Institute for Microbiological Research J-M Wiame (IRMW), Laboratory of Microbiology, Université Libre de Bruxelles, 1, Avenue E. Gryson, Brussels, Belgium;National Fund for Scientific Research, Molecular Biology, GIGA and Gembloux Agro-Bio Tech, Université de Liège, Liège, Belgium;Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium

关键词: Leukemia;    Transformation;    CDK4;    Acetylation;    Tax;    HTLV-1;   

Others  :  1209100
DOI  :  10.1186/1742-4690-10-75

 received in 2013-03-29, accepted in 2013-07-18,  发布年份 2013

【 摘 要 】

Background

Transformation by the Tax oncoprotein of the human T cell leukemia virus type 1 (HTLV-1) is governed by actions on cellular regulatory signals, including modulation of specific cellular gene expression via activation of signaling pathways, acceleration of cell cycle progression via stimulation of cyclin-dependent kinase activity leading to retinoblastoma protein (pRb) hyperphosphorylation and perturbation of survival signals. These actions control early steps in T cell transformation and development of Adult T cell leukemia (ATL), an aggressive malignancy of HTLV-1 infected T lymphocytes. Post-translational modifications of Tax by phosphorylation, ubiquitination, sumoylation and acetylation have been implicated in Tax-mediated activation of the NF-κB pathway, a key function associated with Tax transforming potential.

Results

In this study, we demonstrate that acetylation at lysine K₃₄₆ in the carboxy-terminal domain of Tax is modulated in the Tax nuclear bodies by the acetyltransferase p300 and the deacetylases HDAC5/7 and controls phosphorylation of the tumor suppressor pRb by Tax-cyclin D3-CDK4-p21^CIP complexes. This property correlates with the inability of the acetylation deficient K₃₄₆R mutant, but not the acetylation mimetic K₃₄₆Q mutant, to promote anchorage-independent growth of Rat-1 fibroblasts. By contrast, acetylation at lysine K₃₄₆ had no effects on the ability of Tax carboxy-terminal PDZ-binding domain to interact with the tumor suppressor hDLG.

Conclusions

The identification of the acetyltransferase p300 and the deacetylase HDAC7 as enzymes modulating Tax acetylation points to new therapeutic targets for the treatment of HTLV-1 infected patients at risk of developing ATL.

【 授权许可】

   
2013 Lodewick et al.; licensee BioMed Central Ltd.

【 图 表 】

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