Research article summary (published 29 Sep 2009):

DN-R175H p53 mutation is more effective than p53 interference in inducing epithelial disorganization and activation of proliferation signals in human carcinoma cells: role of E-cadherin.

Full Abstract

One of the hallmarks of carcinomas is epithelial disorganization, linked to overexpression of matrix metalloproteases (MMP) like MMP-9, loss of intercellular E-cadherin and activation of epidermal growth receptor (EGFR/erbB1). Since the p53 tumor suppressor pathway is inactivated in most human cancers due to gene mutations or defective wt p53 signaling, we now investigated in human wt p53 breast carcinoma MCF-7 cells, whether single treatment with the p53 transactivation pharmacological inhibitor pifithrin-alpha, transient p53 siRNA interference or stable insertion of a dominant-negative (DN) R175H p53 mutant increase: (i) EGFR/erbB1 activation, (ii) MMP-9 expression and (iii) loss of surface E-cadherin. Transient abrogation of wt p53 function increased phosphorylation of EGFR/erbB1 and MMP-9 expression. However, all these effects were much more pronounced in cells stably transduced with the dominant negative-Arg-175His mutant p53 (DN-R175H mutant p53), which also showed loss of epithelial cytoarchitecture and extensive E-cadherin downregulation. Collectively, these results support the notion that the DN-R175H mutant p53 exerts a gain of oncogenic function by promoting disruption of E-cadherin intercellular contacts and activation of proliferation signals. Our data suggests that epithelial shape and growth control are unequally affected depending on how wt p53 function is impaired and whether partial or full tumor suppressor activity is lost.

Author information

Author/s: Rieber, Manuel (M); Strasberg Rieber, Mary (M);

Affiliation: Tumor Cell Biology Laboratory, Center for Microbiology and Cell Biology, IVIC, Caracas, Venezuela. mrieber(-atsign-)ivic.ve

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Oct; vol 125 (issue 7) : pp 1604-12

Dates: Created 2009/08/05; Completed 2009/08/28;

PMID: 19507255, status: MEDLINE (last retrieval date: 8/28/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Arginine Breast Neoplasms - metabolism; pathology Cadherins - metabolism Carcinoma - metabolism; pathology Cell Line, Tumor Cell Proliferation Cyclin A - metabolism Down-Regulation Epithelial Cells - metabolism; pathology Female Fluorescent Antibody Technique Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genes, Dominant

Genes, erbB-1 Histidine Humans Immunoblotting Laser Scanning Cytometry Matrix Metalloproteinase 9 - metabolism Mutation Phosphorylation RNA, Small Interfering - metabolism Receptor, Epidermal Growth Factor - genetics; metabolism Retroviridae Transcriptional Activation Transduction, Genetic Tumor Suppressor Protein p53 - genetics; metabolism

Associated Chemicals: Cadherins (0) ; Cyclin A (0) ; RNA, Small Interfering (0) ; Tumor Suppressor Protein p53 (0) ; Histidine (71-00-1) ; Arginine (74-79-3) ; Receptor, Epidermal Growth Factor (EC 2.7.1.112) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)

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