Oncotarget

Research Papers:

Nuclear and cytoplasmic p53 suppress cell invasion by inhibiting respiratory Complex-I activity via Bcl-2 family proteins

Eun Mi Kim, Jong Kuk Park, Sang-Gu Hwang, Wun-Jae Kim, Zheng-Gang Liu, Sang Won Kang and Hong-Duck Um _

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Oncotarget. 2014; 5:8452-8465. https://doi.org/10.18632/oncotarget.2320

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Abstract

Eun Mi Kim1,2, Jong Kuk Park1, Sang-Gu Hwang1, Wun-Jae Kim3, Zheng-Gang Liu4, Sang Won Kang2 and Hong-Duck Um1

1 Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Korea

2 Division of Life and Pharmaceutical Science, Ewha Woman’s University Seoul, Korea

3 Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea

4 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence:

Hong-Duck Um, email:

Keywords: p53, Bcl-2 family proteins, respiratory complex-I, cell invasion

Received: June 27, 2014 Accepted: August 05, 2014 Published: August 06, 2014

Abstract

Although the p53 tumor suppressor/transcription factor often accumulates in the cytoplasm of healthy cells, limited information is available on the cytoplasmic function of p53. Here, we show that cytoplasmic p53 suppresses cell invasion by reducing mitochondrial reactive oxygen species (ROS) levels. Analysis revealed that this function is mediated by Bcl-2 family proteins: Cytoplasmic p53 binds Bcl-w, liberating Bax, which then binds ND5, a subunit of respiratory complex-I, thereby suppressing complex-I activity and thus ROS production. The G13289A mutation of ND5, identified in cancer patients, prevents Bax/ND5 interactions and promotes ROS production and cell invasion. We also showed that Bcl-XL and Bak can substitute for Bcl-w and Bax, respectively, regulating complex-I activity and supporting the cytoplasmic function of p53; nuclear p53 also suppresses complex-I activity by inducing Bax expression. Studies in animal models support the notion that p53 and Bcl-2 family proteins exhibit these functions in vivo. This study demonstrates a link between p53 and Bcl-2 proteins as regulators of ROS production and cellular invasiveness, and reveals complex-I, especially ND5, as their functional target.


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