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- Title
Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.
- Authors
Pande, Sandhya; Browne, Gillian; Padmanabhan, Srivatsan; Zaidi, Sayyed K; Lian, Jane B; van Wijnen, Andre J; Stein, Janet L; Stein, Gary S
- Abstract
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.
- Publication
Journal of cellular physiology, 2013, Vol 228, Issue 8, p1784
- ISSN
1097-4652
- Publication type
Journal Article
- DOI
10.1002/jcp.24339