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Nutlin‐3 activates MEK1/2‐ERK1/2 pathway via p53‐induced ROS accumulation
Author(s) -
Lee Sun-Young,
Ko Kyoung-Won,
Choe Yun-Jeong,
Kim Ho-Shik
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.761.11
Subject(s) - phosphorylation , mdm2 , apoptosis , mapk/erk pathway , gene knockdown , microbiology and biotechnology , small interfering rna , chemistry , cancer research , suppressor , biology , transfection , biochemistry , gene
Tumor suppressor p53 activates growth arrest or apoptosis in response to genotoxic stress. Along with its growth suppressive effect, p53 was also known to stimulate MAPK pathway, of which mechanisms still remains to elusive. In human osteosarcoma U2OS cells, nutlin‐3, a small molecular antagonist of MDM2, induced phosphorylation of MEK1/2 and ERK1/2 accompanied by p53 activation, which was completely inhibited by p53 siRNA. Nutlin‐ 3 induced accumulation of ROS and subsequently, TEMPO, a ROS scavenger, prevented the phosphorylation of MEK1/2 and ERK1/2. Moreover, pifithrin‐μwhich blocks mitochondrial localization of p53 prevented ROS accumulation and MEK1/2‐ ERK1/2 phosphorylation as well. Knockdown of MEK1/2 and ERK1/2 activity using chemical inhibitors or small interfering RNA enhanced cell death induced by nutlin‐3. Collectively, it can be concluded that nutlin‐3 activates MEK1/2‐ERK1/2 via ROS generated by mitochondrial localization of p53 activation and nutlin‐3‐induced ERK1/2 activation may play a role in protecting U20S cells from p53‐dependent apoptosis, constituting negative feedback loop of p53. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011‐ 0027115).