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PAC1 is a direct transcription target of E2F-1 in apoptotic signaling

Oncogene volume 26, pages 6526–6535 (2007)Cite this article

Abstract

E2F-1 controls multiple cellular activities through transcriptional regulation of its target genes. As a mediator of cell death, E2F-1 can eliminate latent neoplastic cells through apoptosis. However, the mechanism by which E2F-1 mediates cancer cell killing is largely unknown. In this paper, we report that phosphatase of activated cells 1 (PAC1) phosphatase is a direct transcription target of E2F-1 in signaling apoptosis. We show that ectopic E2F-1 increases expression of PAC1 at both transcriptional and translational levels in breast cancer cells. E2F-1 physically interacts with the promoter of PAC1, binds to its consensus sequence in the promoter and transactivates the PAC1 promoter. E2F-1 suppresses extracellular signal-regulated kinase (ERK) phosphorylation through PAC1 and causes cancer cell death by apoptosis following treatment with a chemotherapeutic agent N-4-hydroxyphenylretinamide (4-HPR). Furthermore, ectopic PAC1 inhibits ERK phosphorylation and mediates cell killing. Moreover, endogenous E2F-1 upregulates PAC1 and suppresses ERK activity, leading to cell death in response to 4-HPR. These results reveal a crucial role of PAC1 in E2F-1-directed apoptosis. Our study demonstrates that E2F-1 mediates apoptosis through transcriptional regulation of PAC1 and subsequent suppression of the ERK signaling. Our findings establish a functional link between E2F-1 and mitogen-activated protein kinases. The E2F-1–PAC1 cascade in cancer cell killing may provide a molecular basis for cancer therapeutic intervention.

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Acknowledgements

We are grateful to R Baer, HB Lieberman, and PW Brandt-Rauf for critical comments on the manuscript. We thank WH Shen for manuscript preparation and data analysis. W Huang was supported by the Hi-Tech Research and Development Program of China (2006AA02Z489, 2004CB518801). This work was supported by an NIH grant (CA102447) to YY.

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Authors and Affiliations

  1. Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    J Wu, Y J Jin, G M Calaf & Y Yin

  2. State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China

    J Wu & W-L Huang

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  1. J Wu
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Correspondence to Y Yin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wu, J., Jin, Y., Calaf, G. et al. PAC1 is a direct transcription target of E2F-1 in apoptotic signaling. Oncogene 26, 6526–6535 (2007). https://doi.org/10.1038/sj.onc.1210484

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