title: Acetylation at lysine 346 controls the transforming activity of the HTLV-1 Tax oncoprotein in the Rat-1 fibroblast model.
abstract: 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 K(346) 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 K(346)R mutant, but not the acetylation mimetic K(346)Q mutant, to promote anchorage-independent growth of Rat-1 fibroblasts. By contrast, acetylation at lysine K(346) 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.
authors.affiliation: Institute for Microbiological Research J-M Wiame (IRMW), Laboratory of Microbiology, Université Libre de Bruxelles, 1, Avenue E, Gryson, Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Lodewick
authors.forename: Carla
authors.initials: C
authors.lastname: Sampaio
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boxus
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Rinaldi
authors.forename: Katia
authors.initials: K
authors.lastname: Coulonval
authors.forename: Luc
authors.initials: L
authors.lastname: Willems
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Roger
authors.forename: Françoise
authors.initials: F
authors.lastname: Bex
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral; D005347:Fibroblasts / Q000821:virology; D016356:Gene Products, tax / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D016356:Gene Products, tax; D006655:Histone Deacetylases; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C514970:tax protein, Human T-lymphotrophic virus 1; C543273:HDAC7 protein, human