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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Change history
19 May 2009
In the version of this article initially published, The Myc-Ub label in Figure 3c was incorret. Arrowheads were missing in fig. 5d and 5e. A (+) sign was misplaced from the curve in Fig. 7e. These errors have been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank H. K. Sytwu (Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan) for providing the plasmids for the lentivirus infection system, Pei-Fang Hung and Lu-Kai Wang for technical assistance, and Pei-Ying Lin for English language editing. This work was supported by the National Science Council and Department of Health, Executive Yuan of the Republic of China, through the National Research Program for Genomic Medicine Grants (DOH94-TD-G-111-020, DOH95-TD-G-111-010, DOH96-TD-G-111-009, DOH97-TD-G-111-018, DOH98-TD-G-111-007, NSC97-3112-B-002-033 and NSC97-2314-B-002-146-MY3). shRNA constructs were obtained from the National RNAi Core Facility at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica, Taipei, Taiwan.
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T.-M.H. and P.-C.Y. directed the project and contributed equally to this work. S.-P.W. performed and analysed most of the experiments. W.-L.W., Y.-C.C., S.-H.K., S.-C.Y. and W.-K.C. provided reagents and materials, and performed data analysis. Y.-L.C., C.-T.W., A.Y., C.-W.L and K.-C.L. collected and analysed samples from lung cancer patients.
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Wang, SP., Wang, WL., Chang, YL. et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol 11, 694–704 (2009). https://doi.org/10.1038/ncb1875
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DOI: https://doi.org/10.1038/ncb1875
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