title: Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.
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.
authors: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Sandhya
authors: S
authors: Pande
authors: Gillian
authors: G
authors: Browne
authors: Srivatsan
authors: S
authors: Padmanabhan
authors: Sayyed K
authors: SK
authors: Zaidi
authors: Jane B
authors: JB
authors: Lian
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Janet L
authors: JL
authors: Stein
authors: Gary S
authors: GS
authors: Stein
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; D004273:DNA, Neoplasm; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse
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