期刊
TOXICOLOGICAL SCIENCES
卷 148, 期 1, 页码 204-219出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfv182
关键词
antiapoptosis; apoptosis; etoposide; necrosis; p53
类别
资金
- Mid-Career Researcher Program through the National Research Foundation of Korea [2012R1A2A2A02016803]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute [HI14C1992]
- Priority Research Centers Program [NRF 2012-0006687]
- National Research Foundation of Korea [2012R1A2A2A02016803] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The p53 protein is an important transcription factor that modulates signaling pathways for both cell death and survival. Its antiapoptotic mechanisms that correlate with necrotic and apoptotic cell death are not well understood. Here, we report that etoposide promotes progression of the DNA damage response as well as necrotic morphological changes including plasma membrane rupture using carbon nanotube-tipped/atomic force microscopy (CNT/AFM) probes in human kidney proximal tubule (HK-2) cells. Inhibition of p53 abrogated cell cycle arrest and led to a decrease in the expression levels of repair proteins that were induced by DNA damage. Mitochondrial biogenesis and cytosolic production of reactive oxygen species were also reduced after p53 inhibition; the latter change induced mitochondrial superoxide accumulation and mitochondrial damage, which triggered the activation of caspase 3. Inhibition of p53 also led to a loss of cell adhesion and converted necrotic cell death to apoptotic cell death, with appreciable cell shrinkage and appearance of apoptotic bodies that were observed using CNT/AFM probes. Thus, our study demonstrated that p53 protects against apoptosis, and leads to etoposide-induced necrosis. These results are expected to aid in the understanding of mechanism of antiapoptosis and its relationship to cell death.
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