The PDZ domain binding motif (PBM) of human T-cell leukemia virus type 1 Tax can be substituted by heterologous PBMs from viral oncoproteins during T-cell transformation.
Several tumor viruses, such as human T-cell leukemia virus (HTLV), human papilloma virus (HPV), human adenovirus, have high-oncogenic and low-oncogenic subtypes, and such subtype-specific oncogenesis is associated with the PDZ-domain binding motif (PBM) in their transforming proteins. HTLV-1, the causative agent of adult T-cell leukemia, encodes Tax1 with PBM as a transforming protein. The Tax1 PBM was substituted with those from other oncoviruses, and the transforming activity was examined. Tax1 mutants with PBM from either HPV-16 E6 or adenovirus type 9 E4ORF1 are fully active in the transformation of a mouse T-cell line from interleukin-2-dependent growth into independent growth. Interestingly, one such Tax1 PBM mutant had an extra amino acid insertion derived from E6 between PBM and the rest of Tax1, thus suggesting that the amino acid sequences of the peptides between PBM and the rest of Tax1 and the numbers only slightly affect the function of PBM in the transformation. Tax1 and Tax1 PBM mutants interacted with tumor suppressors Dlg1 and Scribble with PDZ-domains. Unlike E6, Tax1 PBM mutants as well as Tax1 did not or minimally induced the degradations of Dlg1 and Scribble, but instead induced their subcellular translocation from the detergent-soluble fraction into the insoluble fraction, thus suggesting that the inactivation mechanism of these tumor suppressor proteins is distinct. The present results suggest that PBMs of high-risk oncoviruses have a common function(s) required for these three tumor viruses to transform cells, which is likely associated with the subtype-specific oncogenesis of these tumor viruses.
Aoyagi
Tomoya
T
Division of Virology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Niigata 951-8510, Japan.
Takahashi
Masahiko
M
Higuchi
Masaya
M
Oie
Masayasu
M
Tanaka
Yuetsu
Y
Kiyono
Tohru
T
Aoyagi
Yutaka
Y
Fujii
Masahiro
M
D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral; D000074288:Discs Large Homolog 1 Protein; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000074407:SAP90-PSD95 Associated Proteins; D013601:T-Lymphocytes / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D000074288:Discs Large Homolog 1 Protein; D016356:Gene Products, tax; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D000074407:SAP90-PSD95 Associated Proteins; D014764:Viral Proteins; C000614189:Dlg1 protein, mouse; C101120:E4 protein, Adenovirus 9; C068651:E6 protein, Human papillomavirus type 16; C508433:scrib protein, mouse; C514970:tax protein, Human T-lymphotrophic virus 1