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p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor

Oncogene volume 20, pages 5818–5825 (2001)Cite this article

Abstract

Recent studies have identified two p53 homologues, p63 and p73. They activate p53-responsive promoters and induce apoptosis when overexpressed in certain human tumors. Here, we report that p63, like p53 and p73, induces replicative senescence when expressed in a tetracycline-regulated manner in EJ cells lacking a functional p53. In addition to transcription activation of p53-responsive genes, we found that p63 and p73 repress transcription of the cdk1 and cyclin B genes, both of which are irreversibly repressed in senescent human fibroblast. In transient transfection assay, p63 and p73 repress the cdk1 promoter regardless of the presence of a dominant negative mutant form of p53. Furthermore, we found that DNA binding activity of NF-Y transcription factor, which is essential for transcription of the cdk1 and cyclin B genes and inactivated in senescent fibroblast, is significantly decreased by expression of either of p53, p63, or p73. Since NF-Y binds to many promoters besides the cdk1 and cyclin B promoters, inactivation of NF-Y by p53 family genes may be a general mechanism for transcription repression in replicative senescence.

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Acknowledgements

We thank Dr Y Ikawa for p63α and p63γ clones, Dr S Uhm for p73α and p73β clones, Dr R Mantovani for antibodies against to NF-Y, Dr K Homma for critical readings of this manuscript. This work was supported in part by the National Research Laboratory Program of the Korean Ministry of Science and Technology (to DY Shin) and the Korean Science and Education Foundation (to DY Shin).

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Author notes

  1. Mun-Su Jung and Jeanho Yun: M Jung and J Yun contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, National Research Laboratory for Cell Cycle Regulation, Dankook University College of Medicine, Chonan, 330-714, Korea

    Mun-Su Jung, Jeanho Yun, Hee-Don Chae, Jeong-Min Kim & Deug Y Shin

  2. Cancer Research Institute, Seoul National University College of Medicine, Jongro-Gu, 103-00, Seoul, Korea

    Mun-Su Jung, Hee-Don Chae & Deug Y Shin

  3. Korea Advanced Institute of Science and Technology, Yusung, 305-333, Taejeon, Korea

    Mun-Su Jung, Jeanho Yun & Sun-Chang Kim

  4. Biotech Research Institute, LG Chem. LTD, Yusung, 305-380, Taejeon, Korea

    Tae-Saeng Choi

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  1. Mun-Su Jung
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Correspondence to Deug Y Shin.

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Jung, MS., Yun, J., Chae, HD. et al. p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor. Oncogene 20, 5818–5825 (2001). https://doi.org/10.1038/sj.onc.1204748

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