Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila discs large tumor suppressor protein, hDLG, and perturbs its function in cell growth control.
HTLV-1 Tax oncoprotein interacts with various cellular factors and modulates transcription and the cell cycle. To identify more cellular targets, we employed the yeast two hybrid system with Tax using a human cDNA library, and isolated a cDNA encoding the human counterpart of Drosophila discs large tumor suppressor protein, hDLG. Tax binding to hDLG was confirmed in vitro and also in HTLV-1-infected T-cells. Furthermore, hDLG was found to be efficiently phosphorylated in Tax-transfected cells and HTLV-1-infected T-cells. The C-terminus of Tax and the PDZ domain of hDLG were responsible for the binding of Tax to hDLG. The C-terminal peptide of Tax prevented the binding of hDLG to APC tumor suppressor gene product, suggesting inhibition of hDLG function by Tax. Over-expression of hDLG in NIH3T3 cells by microinjection induced a reduction of BrdU incorporation into DNA, but co-expression of Tax suppressed this inhibitory effect of hDLG. These results suggest that hDLG arrested the cell cycle and that Tax canceled this inhibitory action of hDLG through targeting hDLG. Therefore, Tax affects this novel regulatory pathway of the cell cycle alteration, of which seems to play a role in the development of human cancer.
Suzuki
T
T
Department of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Ohsugi
Y
Y
Uchida-Toita
M
M
Akiyama
T
T
Yoshida
M
M
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D019476:Insect Proteins / Q000737:chemistry; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D003598:Cytoskeletal Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D029721:Drosophila Proteins; D016356:Gene Products, tax; D019476:Insect Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011506:Proteins; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila