Level of reactive oxygen species induced by p21WAF(1)/CIP(1) is critical for the determination of cell fate

Takafumi Inoue, Kiyoko Kato, Hidenori Kato, Kazuo Asanoma, Ayumi Kuboyama, Yousuke Ueoka, Shin Ichiro Yamaguchi, Tatsuhiro Ohgami, Norio Wake

研究成果: ジャーナルへの寄稿学術誌査読

32 被引用数 (Scopus)

抄録

p21WAF(1)/CIP(1) is a well-known cell cycle regulatory protein which is overexpressed in several cancer cell lines, and known to determine cell fate. We generated three recombinant adenovirus vectors that expressed either the full-length p21 (Ad-p21F), a p21 mutant with a deletion of the C-terminal proliferative cell nuclear antigen (PCNA) binding domain (Ad-p21N), or a p21 mutant with a deletion of the N-terminal cyclin-dependent kinase binding domain (Ad-p21C). We transfected these vectors into five cancer cell lines. Premature senescence was induced in all of the lines only following transfection with Ad-p21N and Ad-p21F. In addition, apoptosis was also induced in LoVo and HCT116 cells that harbored wild-type p53 and the reactive oxygen species (ROS) level was higher than in senescent cells. Finally, the induction of apoptosis was inhibited by using siRNA to downregulate p53. This observation implies that there is a feedback signaling loop involving p21/ROS/p53 in apoptotic responses. It appears to be, at least in part, driven by high levels of p21 protein. Next, we investigated the cell death effect of endogenous p21 protein on cell fate using sodium butyrate (NaB). Treatment with 1 mM NaB or 2 to 5 mM NaB induced senescence or apoptosis, respectively. The level of intracellular ROS in 5 mM NaB treated cells was 2-fold higher, compared with that in 1 mM NaB treated cells. We also demonstrated that DNA damage response signals including ataxia telangiectasia mutated, γH2AX, and p38.MAPK were involved in NaB-induced cell death. The magnitude of intracellular ROS levels in response to p21 elicited either senescence or apoptosis in the cancer cell lines.

本文言語英語
ページ(範囲)1275-1283
ページ数9
ジャーナルCancer Science
100
7
DOI
出版ステータス出版済み - 2009

!!!All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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