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Modulation of nitric oxide‐evoked apoptosis by the p53‐downstream target p21 WAF1/CIP1
Author(s) -
Yang Fan,
Knethen Andreas,
Brüne Bernhard
Publication year - 2000
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.68.6.916
Subject(s) - apoptosis , nitric oxide , biology , cell cycle , cell cycle checkpoint , transfection , microbiology and biotechnology , mediator , cancer research , cell culture , biochemistry , genetics , endocrinology
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.