Human T-cell leukemia virus I tax protein sensitizes p53-mutant cells to DNA damage.
Mutations in p53 are a common cause of resistance of cancers to standard chemotherapy and, thus, treatment failure. Reports have shown that Tax, a human T-cell leukemia virus type I encoded protein that has been associated with genomic instability and perturbation of transcription and cell cycle, sensitizes HeLa cells to UV treatment. The extent to which Tax can sensitize cells and the mechanism by which it exerts its effect are unknown. In this study, we show that Tax sensitizes p53-mutant cells to a broad range of DNA-damaging agents, including mitomycin C, a bifunctional alkylator, etoposide, a topoisomerase II drug, and UV light, but not ionizing radiation, a double-strand break agent, or vinblastine, a tubulin poison. Tax caused hypersensitivity in all p53-deleted cell lines and several, but not all, mutant-expressed p53-containing cell lines, while unexpectedly being protective in p53 wild-type (wt) cells. The effect observed in p53-deleted lines could be reversed for this by transfection of wt p53. We also show that Tax activates a p53-independent proapoptotic program through decreased expression of the retinoblastoma protein and subsequent increased E2F1 expression. The expression of several proapoptotic proteins was also induced by Tax, including Puma and Noxa, culminating in a substantial increase in Bax dimerization. Our results show that Tax can sensitize p53-mutant cells to DNA damage while protecting p53 wt cells, a side benefit that might result in reduced toxicity in normal cells. Such studies hold the promise of a novel adjunctive therapy that could make cancer chemotherapy more effective.
Departments of Microbiology, University of Virginia Health System, Charlottesville, Virginia, USA.
Valia T
VT
Mihaylova
Allison M
AM
Green
Moshe
M
Khurgel
Oliver J
OJ
Semmes
Gary M
GM
Kupfer
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D019281:Dimerization; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014466:Ultraviolet Rays; D014747:Vinblastine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; C494827:Bax protein, mouse; D016356:Gene Products, tax; C498702:PMAIP1 protein, human; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C514970:tax protein, Human T-lymphotrophic virus 1; D016685:Mitomycin; D014747:Vinblastine; D005047:Etoposide; D008156:Luciferases