Transforming Growth Factor-β Stimulates p300-dependent RUNX3 Acetylation, Which Inhibits Ubiquitination-mediated Degradation

Abstract

The Runt domain transcription factors (RUNXs) play essential roles in normal development and neoplasias. Genetic analyses of animals and humans have revealed the involvement of RUNX1 in hematopoiesis and leukemia, RUNX2 in osteogenesis and cleidocranial dysplasia, and RUNX3 in the development of T-cells and dorsal root ganglion neurons and in the genesis of gastric cancer. Here we report that RUNX3 is a target of the acetyltransferase activity of p300. The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation. The extent of the acetylation is up-regulated by the transforming growth factor-␤ signaling pathway and down-regulated by histone deacetylase activities. Our findings demonstrate that the level of RUNX3 protein is controlled by the competitive acetylation and deacetylation of the three lysine residues, revealing a new mechanism for the posttranslational regulation of RUNX3 expression.

Class IIa histone deacetylases: regulating the regulators

“…In this case, the repression of Runx2 activity may rely on the recruitment of class IIa HDACs to Runx2 target promoters through interaction with Smad3 (Kang et al, 2005). Finally, HDAC4 and -5 were reported to directly deacetylate Runx2 and Runx3 which would lead to their ubiquitin-mediated degradation and repression of their transactivation activity (Jin et al, 2004;Jeon et al, 2006). Interestingly, the model that emerges from these observations is dramatically different from what has been established for the regulation of MEF2.…”

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…However, because SMAD and RUNX3 proteins interact (Hanai et al, 1999), it is possible that perturbation of Smad nuclear import/export may promote cytoplasmic accumulation (Inman et al, 2002). Alternatively, a clue can be gleaned from the report that TGF-b stimulates acetylation of RUNX3 protein by p300 and that this inhibits RUNX3 ubiquitination by Smurf1, leading to the stabilization of RUNX3 protein (Jin et al, 2004). It remains to be seen whether acetylated RUNX3 is more efficiently retained in the nucleus.…”

The BMP signaling and in vivo bone formation

“…The conserved PY motif has been identified in all Runx family members. It has been reported that Smurf1 mediates Runx3 degradation in 293 cells and Runx3 with the PY motif mutation is resistant to Smurf1-induced degradation (Jin et al, 2004).…”