p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug
- 17 May 2009
- journal article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 11 (6), 694-704
- https://doi.org/10.1038/ncb1875
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.This publication has 48 references indexed in Scilit:
- The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiationJournal of Bone and Joint Surgery, 2007
- Loss of p53 and Ink4a/Arf Cooperate in a Cell Autonomous Fashion to Induce Metastasis of Hepatocellular Carcinoma CellsCancer Research, 2007
- p53 in health and diseaseNature Reviews Molecular Cell Biology, 2007
- Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasionOncogene, 2006
- Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patientsBritish Journal of Cancer, 2006
- Complex networks orchestrate epithelial–mesenchymal transitionsNature Reviews Molecular Cell Biology, 2006
- Expression of the Transcription Factors Snail, Slug, and Twist and Their Clinical Significance in Human Breast CancerAnnals of Surgical Oncology, 2005
- The Absence of p53 Promotes Metastasis in a Novel Somatic Mouse Model for Hepatocellular CarcinomaMolecular and Cellular Biology, 2005
- Assessing TP53 status in human tumours to evaluate clinical outcomeNature Reviews Cancer, 2001
- Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elementsOncogene, 1999