4.5 Article

Gain of oncogenic function of p53 mutants regulates E-cadherin expression uncoupled from cell invasion in colon cancer cells

期刊

JOURNAL OF CELL SCIENCE
卷 123, 期 8, 页码 1295-1305

出版社

COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.061002

关键词

p53; E-cadherin; Epithelial-to-mesenchymal transition; Invasion; Metastasis

资金

  1. CNRS
  2. Fondation de France
  3. Association pour la Recherche contre le Cancer [ARC 4028]
  4. la Ligue contre le Cancer de L'Herault
  5. Ministere de l'Education Nationale et de la Recherche
  6. ARC and Societe du Cancer

向作者/读者索取更多资源

Mutations in the p53 tumour suppressor gene are associated clinically with tumour progression and metastasis. Downregulation of the E-cadherin cell-cell adhesion molecule is a key event for epithelial to mesenchymal transition (EMT) in tumour progression. Here, we show that wild-type p53 induced to adopt a mutant conformation, and hot-spot p53 mutants, which are both transcriptionally inactive, downregulate E-cadherin expression in the colon carcinoma cell line HCT116. Downregulation of E-cadherin occurred concomitantly with the upregulation of Slug and Zeb-1, transcriptional factors known to repress E-cadherin gene expression. In addition, knockdown of Slug and Zeb-1 expression diminished p53-mediated E-cadherin repression. Knocking down endogenous mutant p53 in MDA-MB-231 and SW620 cancer cell lines lacking E-cadherin protein restored the expression of E-cadherin. Complete loss of E-cadherin expression in HCT116 cells induced morphological alterations along with upregulation of vimentin, a mesenchymal marker. These changes characteristic of the EMT phenotype were, however, not sufficient to confer invasiveness in a three-dimensional matrix. Downregulation of E-cadherin by mutant p53 was not required to promote the invasive phenotype induced by inactivation of p53. These findings indicate that independent control of E-cadherin expression and cell motility could be essential molecular events in p53 mutant-induced invasive phenotypes.

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