Document Detail


Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.
MedLine Citation:
PMID:  23389849     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer-related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA-binding activity of Runx2 with concomitant reduction in the expression of metastasis-related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA-binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA-binding activity. However, Akt signaling does not appear to interefere with CBFβ-Runx2 interactions. Consequently, expression of multiple metastasis-related genes is decreased and Runx2-mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells.
Authors:
Sandhya Pande; Gillian Browne; Srivatsan Padmanabhan; Sayyed K Zaidi; Jane B Lian; Andre J van Wijnen; Janet L Stein; Gary S Stein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  228     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-04-22     Completed Date:  2013-06-24     Revised Date:  2013-08-27    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1784-92     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
Affiliation:
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites / genetics
Breast Neoplasms / genetics,  metabolism*,  secondary*
Cell Line, Tumor
Core Binding Factor Alpha 1 Subunit / genetics,  metabolism*
Core Binding Factor beta Subunit / metabolism
DNA, Neoplasm / metabolism
Female
Humans
Male
Mammary Neoplasms, Experimental / metabolism,  pathology
Mice
Mice, Transgenic
Mutagenesis, Site-Directed
Neoplasm Invasiveness / genetics,  pathology
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  metabolism*
Phosphorylation
Proto-Oncogene Proteins c-akt / antagonists & inhibitors,  metabolism*
Signal Transduction
Grant Support
ID/Acronym/Agency:
5P01 CA140043/CA/NCI NIH HHS; P01 AR048818/AR/NIAMS NIH HHS; P01 AR048818/AR/NIAMS NIH HHS; P01 CA082834/CA/NCI NIH HHS; P01 CA082834/CA/NCI NIH HHS; R01 AR039588/AR/NIAMS NIH HHS; R01 AR039588/AR/NIAMS NIH HHS; R01 AR049069/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Core Binding Factor Alpha 1 Subunit; 0/Core Binding Factor beta Subunit; 0/DNA, Neoplasm; 0/RUNX2 protein, human; 0/Runx2 protein, mouse; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt

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