Research Papers:

Modulation of the Nur77-Bcl-2 apoptotic pathway by p38α MAPK

Jie Liu, Guang-Hui Wang, Ying-Hui Duan, Yi Dai, Yuzhou Bao, Mengjie Hu, Yu-Qi Zhou, Mingyu Li, Fuquan Jiang, Hu Zhou, Xin-Sheng Yao and Xiao-Kun Zhang _

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Oncotarget. 2017; 8:69731-69745. https://doi.org/10.18632/oncotarget.19227

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Jie Liu1,*, Guang-Hui Wang1,*, Ying-Hui Duan2, Yi Dai2, Yuzhou Bao1, Mengjie Hu1, Yu-Qi Zhou1, Mingyu Li1, Fuquan Jiang1, Hu Zhou1, Xin-Sheng Yao2 and Xiao-Kun Zhang1,3

1School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, China

2Institutes of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou, China

3Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA

*These authors contributed equally to this work

Correspondence to:

Xiao-Kun Zhang, email: [email protected]

Xin-Sheng Yao, email: [email protected]

Keywords: CCE9, Nur77, Bcl-2, p38α MAPK, apoptosis

Received: March 01, 2017     Accepted: June 05, 2017     Published: July 13, 2017


Orphan nuclear receptor Nur77 promotes apoptosis by targeting mitochondria through interaction with Bcl-2, an event that converts Bcl-2 from a survival to killer. However, how the Nur77-Bcl-2 apoptotic pathway is regulated remains largely unknown. In this study, we examined the regulation of the Nur77-Bcl-2 pathway by CCE9, a xanthone compound. Our results demonstrated that the apoptotic effect of CCE9 depended on its induction of Nur77 expression, cytoplasmic localization, and mitochondrial targeting. The activation of the Nur77-Bcl-2 pathway by CCE9 was associated with its activation of p38α MAPK. Inhibition of p38α MAPK activation by knocking down or knocking out p38α MAPK impaired the effect of CCE9 on inducing apoptosis and the expression and cytoplasmic localization of Nur77. In addition, CCE9 activation of p38α MAPK resulted in Bcl-2 phosphorylation and Bcl-2 interaction with Nur77, whereas inhibition of p38α MAPK activation or expression suppressed the interaction. Moreover, mutating Ser87 and Thr56 in the loop of Bcl-2, which are known to be phosphorylated by p38α MAPK, impaired the ability Bcl-2 to interact with Nur77. Together, our results reveal a profound role of p38α MAPK in regulating the Nur77-Bcl-2 apoptotic pathway through its modulation of Nur77 expression, Bcl-2 phosphorylation, and their interaction.

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