Modulation of nitric oxide-evoked apoptosis by the p53-downstream target p21(WAF1/CIP1).
When produced in excess, the inflammatory mediator nitric oxide (NO) attenuates cell-cycle progression at the G1 phase in tight correlation with p21(WAF1/CIP1) expression, provokes accumulation of the tumor suppressor p53, and initiates apoptosis/necrosis as judged on cell accumulation in the sub-G1 phase. To verify the role of p21(WAF1/CIP1) in modulating cell-cycle arrest vs. apoptosis, we transfected stably antisense p21(WAF1/CIP1)-encoding plasmids. Following NO exposure, accumulation of p21(WAF1/CIP1), but not p53, was largely attenuated in antisense p21(WAF1/CIP1) transfectants. Moreover, the G1 cell-cycle arrest was abrogated, and cells were sensitized toward apoptosis compared with parent macrophages. In contrast, antisense elimination of p53 attenuated p53 as well as p21(WAF1/CIP1) expression, abolished the G1 cell-cycle arrest, and prevented apoptosis. We conclude that p21(WAF1/CIP1) is a downstream target of p53 in macrophages that modulate the sensitivity toward the immune-modulator NO.
Yang
F
F
University of Erlangen-Nürnberg, Faculty of Medicine, Department of Medicine IV, Erlangen, Germany.
von Knethen
A
A
Brüne
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D026422:S-Nitrosoglutathione; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D020319:Oligodeoxyribonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005978:Glutathione