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Foxp3 is a key downstream regulator of p53-mediated cellular senescence

Oncogene volume 36, pages 219–230 (2017)Cite this article

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Abstract

The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-l-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.

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Gene Expression Omnibus

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Acknowledgements

This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2013233), and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (NRF-2013R1A2A2A01067394), Seoul, Republic of Korea. The National Research Foundation of Korea Grant funded by the Korea Government (Ministry of Education, Science and Technology) (NRF-2010-355-C00062).

Accession numbers: The full microarray data set has been deposited in the Gene Expression Omnibus (GEO) database under submission number GSE71980.

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Author notes

  1. J-E Kim, J-S Shin and J-H Moon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea

    J-E Kim, D-J Jung & W-J Lee

  2. Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea

    J-S Shin, J-H Moon, S-W Hong, J H Kim, I-Y Hwang, Y J Shin, E-Y Gong, D H Lee, S-M Kim, E Y Lee, T W Kim, K-p Kim & D-H Jin

  3. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

    J-S Shin, J-H Moon, S-W Hong, J H Kim, I-Y Hwang, Y J Shin, E-Y Gong, D H Lee, S-M Kim, E Y Lee, T W Kim, K-p Kim & D-H Jin

  4. Department of Anatomy and Research Center for Tumor Immunology, Inje University College of Medicine, Busan, Republic of Korea

    Y S Kim, D Kim & D Hur

  5. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

    D-H Jin

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Correspondence to K-p Kim or D-H Jin.

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Kim, JE., Shin, JS., Moon, JH. et al. Foxp3 is a key downstream regulator of p53-mediated cellular senescence. Oncogene 36, 219–230 (2017). https://doi.org/10.1038/onc.2016.193

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