Dose-dependent dual effect of HTLV-1 tax oncoprotein on p53-dependent nucleotide excision repair in human T-cells.
In this study we investigated the effect of Tax on nucleotide excision repair (NER) in human T-cell lines by using the host cell repair analysis of UVC-irradiated reporter plasmid. This analysis revealed a p53-dependent NER activity in wild type (w.t.) p53-containing T-cells and p53-independent NER in w.t. p53-lacking T-cells. Notably, in the w.t. p53-containing cells Tax exerted a dose-dependent dual effect on NER. While low Tax doses markedly stimulated this repair, high Tax doses strongly reduced it. Further experiments demonstrated that the low Tax doses enhanced, in these cells, the level and the transcriptional function of their w.t. p53 protein. On the other hand, although the high Tax doses further increased the level of p53, they functionally inactivated its accumulating molecules. Both of these Tax effects on p53 proved to be mediated by Tax-induced NF-kappaB-related mechanisms. Together, these data suggest that by NF-kappaB activation Tax elevates the level of the cellular w.t. p53. However, while at low Tax doses the elevating w.t. p53 molecules are functionally active and capable of stimulating NER, intensifying further the NF-kappaB activation by the high Tax doses concomitantly evokes certain mechanism(s) which functionally inactivates the accumulating p53 protein. In contrast to this dual effect on the p53-dependent NER, Tax displayed only an inhibitory effect on the p53-independent NER by its high doses, whereas its low doses had no effect on this repair. The mechanisms of the NF-kappaB-associated effects on the level and function of the cellular w.t.p53 and of the p53-independent NER noted in our experimental systems are further investigated in our laboratory.
Schavinsky-Khrapunsky
Yana
Y
The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and Cancer Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Priel
Esther
E
Aboud
Mordechai
M
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D016356:Gene Products, tax / Q000378:metabolism / Q000502:physiology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016356:Gene Products, tax; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53