title: P53 facilitates degradation of human T-cell leukaemia virus type I Tax-binding protein through a proteasome-dependent pathway.
abstract: Human T-cell leukaemia virus type 1 (HTLV-I), the aetiological agent of adult T-cell leukaemia (ATL) and tropical spastic paraparesis (TSP/HAM), transforms human T-cells in vivo and in vitro. The Tax protein of HTLV-I is essential for cellular transformation as well as viral and cellular gene transactivation. The interaction of Tax with cellular proteins is critical for these functions. We previously isolated and characterized a novel Tax-binding protein, TRX (TAX1BP2), by screening a Jurkat T-cell cDNA library. In the present study, we present evidence that the tumour suppressor p53 targets the TRX protein for proteasome degradation. Pulse-chase experiments revealed that p53 enhanced the degradation of TRX protein and reduced the half-life from 2.0 to 0.25 h. p53 mutants R248W and R273H enhance TRX degradation suggesting a transcriptionally independent mechanism. Both HTLV-I Tax and the proteasome-specific inhibitor MG132 inhibited p53-mediated TRX protein degradation. These results suggest that TRX degradation is mediated through activation of the proteasome protein degradation pathway independent of transcriptional function of p53. Our results provide the first experimental evidence that Tax inhibits transcription-dependent and independent functions of p53.
authors.affiliation: Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Iqbal H
authors.initials: IH
authors.lastname: Chowdhury
authors.affiliation: Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Radonovich
authors.affiliation: Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France.|Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Renaud
authors.initials: R
authors.lastname: Mahieux
authors.affiliation: Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Pise-Masison
authors.affiliation: Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Muralidhar
authors.affiliation: Virus Tumor Biology Section, Basic Research Laboratory, National Cancer Institute, National Institutes of Health, Building 41/B201, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Brady
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016356:Gene Products, tax / Q000378:metabolism* / Q000494:pharmacology; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins / Q000494:pharmacology; D008565:Membrane Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D016356:Gene Products, tax; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; C494631:VAC14 protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde