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Regulation of p53 stability by Mdm2

Author

Listed:
  • Michael H. G. Kubbutat

    (NCI-FCRDC)

  • Stephen N. Jones

    (Baylor College of Medicine)

  • Karen H. Vousden

    (NCI-FCRDC)

Abstract

The tumour-suppressor p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Stabilization of the protein in response to an activating signal, such as DNA damage, results in a rapid rise in p53 levels and subsequent inhibition of cell growth1. Tight regulation of p53 function is critical for normal cell growth and development, and one mechanism by which p53 function is controlled is through interaction with the Mdm2 protein2–4. Mdm2 inhibits p53 cell-cycle arrest and apoptic functions5,6 and we show here that interaction with Mdm2 can also result in a large reduction in p53 protein levels through enhanced proteasome-dependent degradation. Endogenous levels of Mdm2 are sufficient to regulate p53 stability, and overexpres-sion of Mdm2 can reduce the amount of endogenous p53. Because mdm2 is transcriptionally activated by p53 (refs 7, 8), this degradative pathway may contribute to the maintenance of low p53 concentrations in normal cells. Furthermore, mechanisms regulating the Mdm2-induced degradation of p53 may play a role in controlling the extent and duration of the p53 response.

Suggested Citation

  • Michael H. G. Kubbutat & Stephen N. Jones & Karen H. Vousden, 1997. "Regulation of p53 stability by Mdm2," Nature, Nature, vol. 387(6630), pages 299-303, May.
    • Handle: RePEc:nat:nature:v:387:y:1997:i:6630:d:10.1038_387299a0
    DOI: 10.1038/387299a0
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    Cited by:

    1. Mu Li & Aaron Zhong & Youjun Wu & Mega Sidharta & Michael Beaury & Xiaolan Zhao & Lorenz Studer & Ting Zhou, 2022. "Transient inhibition of p53 enhances prime editing and cytosine base-editing efficiencies in human pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Jing Li & Yang Tang & Liu Huang & Qianqian Yu & Guangyuan Hu & Xianglin Yuan, 2016. "Genetic Variants in the p14ARF/MDM2/TP53 Pathway Are Associated with the Prognosis of Esophageal Squamous Cell Carcinoma Patients Treated with Radical Resection," PLOS ONE, Public Library of Science, vol. 11(7), pages 1-11, July.
    3. Masayo Inoue & Katsuhisa Horimoto, 2017. "Relationship between regulatory pattern of gene expression level and gene function," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-14, May.
    4. Ying-Yu Ma & Tian-Pei Guan & Hai-Bo Yao & Sheng Yu & Le-Gao Chen & Ying-Jie Xia & Xu-Jun He & Hui-Ju Wang & Xiao-Ting Jiang & Hou-Quan Tao, 2013. "The MDM2 309T>G Polymorphism and Ovarian Cancer Risk: A Meta-Analysis of 1534 Cases and 2211 Controls," PLOS ONE, Public Library of Science, vol. 8(1), pages 1-6, January.
    5. Bo Liu & Shiwei Yan & Xingfa Gao, 2011. "Noise Amplification in Human Tumor Suppression following Gamma Irradiation," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-9, August.
    6. Tomoe Ueyama & Shu Nakao & Tasuku Tsukamoto & Dai Ihara & Yukihiro Harada & Yuka Akagi & Sae Nakagawa & Teruhisa Kawamura & Takahiro Sogo & Yasuyuki S Kida, 2018. "PTEN/Akt Axis is Involved in Somatic Cell Reprogramming to Mouse iPS Cells," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 11(5), pages 8789-8795, December.
    7. Clara Morral & Arshad Ayyaz & Hsuan-Cheng Kuo & Mardi Fink & Ioannis I. Verginadis & Andrea R. Daniel & Danielle N. Burner & Lucy M. Driver & Sloane Satow & Stephanie Hasapis & Reem Ghinnagow & Lixia , 2024. "p53 promotes revival stem cells in the regenerating intestine after severe radiation injury," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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