Co‐activator activator (CoAA) prevents the transcriptional activity of Runt domain transcription factors

Abstract

Runx proteins are essential for a number of developmental processes and are aberrantly expressed in many human cancers. Runx factors bind DNA and co-factors to activate or repress genes crucial for bone formation, hematopoiesis, and neuronal development. Co-activator activator (CoAA) is a nuclear protein that regulates gene expression, RNA splicing and is overexpressed in many human tumors. In this study, we identified CoAA as a Runx2 binding protein. CoAA repressed Runx factor-dependent activation of reporter genes in a histone deacetylase-independent manner. CoAA also blocked Runx2-mediated repression of the Axin2 promoter, a novel Runx target gene. The carboxy-terminus of CoAA is essential for binding the Runt domains of Runx1 and Runx2. In electophoretic mobility shift assays, CoAA inhibited Runx2 interactions with DNA. These data indicate that CoAA is an inhibitor of Runx factors and can negate Runx factor regulation of gene expression. CoAA is expressed at high levels in human fetal osteoblasts and osteosarcoma cell lines. Suppression of CoAA expression by RNA interference reduced osteosarcoma cell viability in vitro, suggesting that it contributes to the proliferation and/or survival of osteoblast lineage cells.

The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics

“…47 Therefore, instead of therapeutics targeting SHH, which has important, potential clinical limitations of teratogenicity, RUNX1 may serve as a potential therapeutic target. Recently, Li et al 48 have shown that the nuclear protein Co-activator activator can bind to RUNX proteins and interfere with their activity, perhaps ultimately acting as an alternative avenue to blocking the downstream effects of SHH signaling.…”

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

“…It has been reported that Runx2 is a direct phosphorylation target for PKA (22); nevertheless, increases in Runx2 phosphorylation were not detected in either control or knockdown cells (data not shown). Previous studies have also indicated that the transcriptional activity of Runx2 can be modulated by binding to other nuclear proteins, including transcriptional coactivators, corepressors, and other transcription factors (23)(24)(25). As examples of the latter with relevance to osteogenesis, the Foxo1 protein was found to interact directly with Runx2, and Atf4 could indirectly associate with Runx2 in MC3T3-E1 cells to regulate osteocalcin gene expression (26 -29).…”

TEThered to Runx: Novel binding partners for runx factors

“…Actinin, EPLIN, gelsolin and HSP70 were some of the proteins eluted from TAP-Runx2 immune-complexes and identified with mass spectroscopy. Ddx5 (p68), Ddx17 (p72), and co-activator activator (CoAA) also bound to TAP-Runx2 and were verified as Runx2 binding partners and cofactors in subsequent assays [6; 7]. Ddx5 and CoAA each co-localized with Runx2 in subnuclear structures and interacted with Runx2.…”