p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug
Abstract
The tumour suppressor p53 is known to prevent cancer progression by inhibiting proliferation and inducing apoptosis of tumour cells. Slug, an invasion promoter, exerts its effects by repressing E-cadherin transcription. Here we show that wild-type p53 (wtp53) suppresses cancer invasion by inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In non-small-cell lung cancer (NSCLC), mutation of p53 correlates with low MDM2, high Slug and low E-cadherin expression. This expression profile is associated with poor overall survival and short metastasis-free survival in patients with NSCLC. wtp53 upregulates MDM2 and forms a wtp53-MDM2-Slug complex that facilitates MDM2-mediated Slug degradation. Downregulation of Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer cell invasiveness. In contrast, mutant p53 inactivates Slug degradation and leads to Slug accumulation and increased cancer cell invasiveness. Our findings indicate that wtp53 and p53 mutants may differentially control cancer invasion and metastasis through the p53-MDM2-Slug pathway.
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In cell culture, Mdm2 lowers Slug and raises E-cadherin.
“Furthermore, Mdm2 was recently reported to downregulate Slug and increase E-cadherin in cell culture, which would presumably prevent invasiveness [101].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [101]
The ability of Mdm2 to lower Slug and raise E-cadherin would presumably make cells less invasive.
“Furthermore, Mdm2 was recently reported to downregulate Slug and increase E-cadherin in cell culture, which would presumably prevent invasiveness [101].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [101]
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- Authors
- Wang, S.-P., Wang, W.-L., Chang, Y.-L., Wu, C.-T., Chao, Y.-C., Kao, S.-H., Yuan, A., Lin, C.-W., Yang, S.-C., Chan, W.-K., Li, K.-C., Hong, T.-M., & Yang, P.-C.
- Affiliations
- National Defense Medical Center (TW)
- National Taiwan University (TW)
- National Taiwan University Hospital (TW)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Institute of Statistical Science, Academia Sinica (TW)
- National Cheng Kung University (TW)
- Corresponding author
- Yang, Pan-Chyr
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2009-05-17
- Volume
- 11
- Issue
- 6
- Pages
- 694-704
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2002376765
- Cited by
- 493
- References
- 49
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 21 · 2023: 30 · 2022: 26 · 2021: 46 · 2020: 33 · 2019: 35 · 2018: 26 · 2017: 27 · 2016: 31 · 2015: 32 · 2014: 26 · 2013: 37 · 2012: 27
- FWCI
- 17.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- World Health Organization
- National Taiwan University Hospital
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- p53, Slug, MDM2, protein degradation, tumor invasion, metastasis, E-cadherin, non-small cell lung cancer, mutant p53, tumour suppressor, transcriptional repression
- MeSH terms
- Snail Family Transcription Factors, Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Neoplasm Invasiveness, Neoplasm Metastasis, Transcription Factors, Cadherins, Survival Rate, Tumor Suppressor Protein p53, Cell Line, Tumor, Mice, Proto-Oncogene Proteins c-mdm2
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