Identification of the interferon-inducible double-stranded RNA-dependent protein kinase as a regulator of cellular response to bulky adducts.
The double-stranded RNA-dependent protein kinase PKR plays a central role in IFN-mediated antiviral response. The ability of PKR mutants to transform rodent fibroblasts led to the hypothesis that PKR acts as a tumor suppressor. Recent studies have identified an expanding network of PKR signaling partners, including signal transducers and activators of transcription 1 (STAT1), p53, and IkappaB-kinase. Here we demonstrate that PKR is involved in the cellular response to genotoxic stress. PKR-deficient mouse-embryonic fibroblasts (PKR-/-) are hypersensitive to bulky adduct DNA damage caused by cisplatin, melphalan, and UV radiation but not to other DNA-damaging agents such as Adriamycin. PKR-deficient cells are highly susceptible to cisplatin-induced apoptosis. They demonstrate retarded cisplatin adduct removal kinetics. Most strikingly, PKR localizes to the nucleus rapidly upon cisplatin treatment. Restoration of PKR in PKR-/- cells results in resistance to cisplatin and enhanced cell capacity to remove cisplatin DNA adducts. We conclude that PKR has a function in the regulation of cellular response to bulky adduct-inducing agents, possibly by modulating DNA repair mechanisms.
Bergeron
J
J
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada.
Benlimame
N
N
Zeng-Rong
N
N
Xiao
D
D
Scrivens
P J
PJ
Koromilas
A E
AE
Alaoui-Jamali
M A
MA
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics; D017209:Apoptosis; D002945:Cisplatin / Q000493:pharmacokinetics; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007372:Interferons / Q000378:metabolism*; D007700:Kinetics; D008558:Melphalan / Q000493:pharmacokinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D012330:RNA, Double-Stranded / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D012330:RNA, Double-Stranded; D004317:Doxorubicin; D004247:DNA; D007372:Interferons; D019892:eIF-2 Kinase; D002945:Cisplatin; D008558:Melphalan