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Protective effect of Homer 1a on tumor necrosis factor-α with cycloheximide-induced apoptosis is mediated by mitogen-activated protein kinase pathways

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Abstract

Although Homer 1, of the postsynaptic density, regulates apoptosis, the signaling mechanisms are not fully elucidated. In this study, we found that tumor necrosis factor-α (TNF-α)/cycloheximide (CHX) treatment transiently increased Homer 1a (the short variant of Homer 1), but did not affect Homer 1b/c (the long variant of Homer 1). Overexpression of Homer 1a blocked TNF-α/CHX-induced apoptotic cell death, whereas inhibition of Homer 1a induction enhanced the pro-apoptotic effect of TNF-α/CHX treatment. Moreover, brain-derived neurotrophic factor, as a potential activator of endogenous Homer 1a, inhibited apoptotic cell death after TNF-α/CHX treatment through induction of Homer 1a. Since three major mitogen-activated protein kinase (MAPK) pathways have important roles in apoptosis, we examined if Homer 1a is involved in the effects of MAPK pathways on apoptosis. It was shown that inhibition of the ERK1/2 pathway increased the expression and the protective effect of Homer 1a, but inhibition of the p38 pathway produced the opposite effect. Cross-talk among MAPK pathways was also associated with the regulation of Homer 1a during apoptotic cell death. Blocking the p38 pathway increased the activity in the ERK1/2 pathway, while inhibition of ERK1/2 pathway abolished the effect of p38 inhibitor on Homer 1a. Furthermore, Homer 1a reversely affected the activation of MAPK pathways. These findings suggest that Homer 1a plays an important role in the prevention of apoptotic cell death and contributes to distinct regulatory effects of MAPK pathways on apoptotic cell death.

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Acknowledgments

We would like to give our thanks to Ning Su, Yihui Ma, Kai Wang, Junli Huo, Juan Li, Xiaoyan Chen, and Yufen Shi for technical assistance. The work was supported by National Natural Science Foundation of China (Nos. 30670796, 30930093) and the 863 High-Tech Project (2009AA02Z419).

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Authors and Affiliations

  1. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 15 Changle Xi Road, Xian, 710032, People’s Republic of China

    Peng Luo, Yongbo Zhao, Dong Li, Tao Chen, Sanzhong Li, Xiaodong Chao, Wenbo Liu, Lei Zhang, Yan Qu, Xiaofan Jiang & Zhou Fei

  2. Divison of Neurosurgery, Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin NT, Hong Kong, People’s Republic of China

    Gang Lu & Waisang Poon

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  1. Peng Luo
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Correspondence to Waisang Poon or Zhou Fei.

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Luo, P., Zhao, Y., Li, D. et al. Protective effect of Homer 1a on tumor necrosis factor-α with cycloheximide-induced apoptosis is mediated by mitogen-activated protein kinase pathways. Apoptosis 17, 975–988 (2012). https://doi.org/10.1007/s10495-012-0736-z

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