Document Detail


Mutant p53 disrupts MCF-10A cell polarity in three-dimensional culture via epithelial-to-mesenchymal transitions.
MedLine Citation:
PMID:  21454711     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutant p53 is not only deficient in tumor suppression but also acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knock-in mice that carry one null allele and one mutant allele of the p53 gene. These knock-in mice develop aggressive tumors compared with p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for cell survival and resistance to DNA damage. To further define mutant p53 gain of function, we used the MCF-10A three-dimensional model of mammary morphogenesis. MCF-10A cells in three-dimensional culture undergo a series of morphological changes and form polarized and growth-arrested spheroids with hollow lumen, which resembles normal glandular architectures in vivo. Here, we found that endogenous wild-type p53 in MCF-10A cells was not required for acinus formation, but knockdown of endogenous wild-type p53 (p53-KD) led to partial clearance of cells in the lumen due to decreased apoptosis. Consistent with this, p53-KD altered expression patterns of the cell adhesion molecule E-cadherin, the cytoskeletal marker β-catenin, and the extracellular matrix protein laminin V. We also found that ectopic expression of the mutant G245S led to a phenotype similar to p53-KD, whereas a combination of ectopic expression of siRNA-resistant G245S with p53-KD led to a less cleared lumen. In contrast, ectopic expression of mutant R248W, R175H, and R273H disrupted normal acinus architectures with filled lumen and led to formation of irregular and multiacinus structures regardless of p53-KD. In addition, these mutants altered normal expression patterns and/or levels of E-cadherin, β-catenin, laminin V, and tight junction marker ZO-1. Furthermore, epithelial-to-mesenchymal transitions (EMT) markers, Snail, Slug, and Twist, were highly induced by mutant p53 and/or p53-KD. Together, we postulate that EMT represents a mutant p53 gain of function and mutant p53 alters cell polarity via EMT.
Authors:
Yanhong Zhang; Wensheng Yan; Xinbin Chen
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-02     Completed Date:  2011-07-01     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16218-28     Citation Subset:  IM    
Affiliation:
Comparative Oncology Laboratory, University of California, Davis, California 95616, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alleles
Amino Acid Substitution
Animals
Cadherins / genetics,  metabolism
Cell Adhesion Molecules / genetics,  metabolism
Cell Line, Tumor
Cell Polarity*
Cell Survival / genetics
Epithelial-Mesenchymal Transition*
Female
Membrane Proteins / genetics,  metabolism
Mice
Mice, Transgenic
Mutation, Missense*
Phosphoproteins / genetics,  metabolism
Transcription Factors / genetics,  metabolism
Tumor Suppressor Protein p53 / genetics,  metabolism*
Twist Transcription Factor / genetics,  metabolism
Zonula Occludens-1 Protein
beta Catenin / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA121137/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Cadherins; 0/Cell Adhesion Molecules; 0/Membrane Proteins; 0/Phosphoproteins; 0/Tjp1 protein, mouse; 0/Transcription Factors; 0/Tumor Suppressor Protein p53; 0/Twist Transcription Factor; 0/Zonula Occludens-1 Protein; 0/beta Catenin; 0/kalinin; 0/snail family transcription factors
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Differences between human and rodent pancreatic islets: low pyruvate carboxylase, atp citrate lyase,...
Next Document:  Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells.