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Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes

Oncogene volume 23, pages 7310–7321 (2004)Cite this article

Abstract

The proto-oncogene, bcl-2, has various functions besides its role in protecting cells from apoptosis. One of the functions is to regulate expression of other genes. Previous studies have demonstrated that Bcl-2 regulates activities of several important transcription factors including NF-κB and p53, and also their downstream genes. In our recent studies, we reported that Bcl-2 substantially downregulates expression of the endogenous αB-crystallin gene through modulating the transcriptional activity of lens epithelium-derived growth factor (LEDGF). In the present communication, we report that human Bcl-2 can positively regulate expression of the proto-oncogenes c-jun and c-fos. Moreover, it enhances the DNA binding activity and transactivity of the activating protein-1 (AP-1). Furthermore, we present evidence to show that Bcl-2 can also activate both ERK1 and ERK2 MAP kinases. Inhibition of the activities of these kinases or the upstream activating kinases by pharmacological inhibitors or dominant-negative mutants abolishes the Bcl-2-mediated regulation of AP-1, LEDGF and their downstream genes. Together, our results demonstrate that through activation of the ERK kinase signaling pathway, Bcl-2 regulates the transcriptional activities of multiple transcription factors, and hence modulates the expression of their downstream genes. Thus, our results provide a mechanism to explain how Bcl-2 may regulate expression of other genes.

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Acknowledgements

We thank Dr Stanley Korsmeyer for the human Bcl-2 expression construct, Dr Tom Curran for the rat c-jun and c-fos cDNA clones, Dr Meng-Sheng Qiu for the GAPDH cDNA, Dr John Westwick for the luciferase reporter gene expression construct, Dr John Reddan for the RLECs (N/N1003A) and Dr Joram Piatigorsky for the chicken βA3/A1-CAT and pRSV-β-galactosidase expression constructs. This work was partially supported by NIH/NEI 11372, the Hormel Foundation, University of Minnesota Graduate School, and the Lotus Scholar Program Funds from Hunan Province Government and Hunan Normal University.

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Author notes

  1. Hua Xiang

    Present address: State Key Laboratory of Microbial Resources and Center for Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100080, PR China

  2. Ying-Wei Mao

    Present address: Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA

  3. Juan Wang

    Present address: Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics and The Penn Diabetes Center, University of Pennsylvania, Philadelphia, PA, 19104, USA

Authors and Affiliations

  1. College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR China

    Hao Feng, Xiao-Qin Huang, Yan Liu, Shao-Jun Liu, Chen Luo, Xuan-Jie Zhang, Yun Liu & David Wan-Cheng Li

  2. Department of Molecular Biology, University of Medicine and Dentistry of New Jersey, Stratford, NJ, USA

    Hua Xiang, Ying-Wei Mao, Juan Wang & David Wan-Cheng Li

  3. The Hormel Institute, University of Minnesota, Austin, MN, USA

    Jin-Ping Liu & David Wan-Cheng Li

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Correspondence to David Wan-Cheng Li.

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Feng, H., Xiang, H., Mao, YW. et al. Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes. Oncogene 23, 7310–7321 (2004). https://doi.org/10.1038/sj.onc.1208041

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