Abstract 3062: Ada3, a component of STAGA HAT complex, controls cell cycle by regulating c-myc

Abstract

Abstract The human homologue of the yeast Ada3 (alteration/deficiency in activation) protein is an essential component of various Histone acetyl transferase complexes (HATs). To gain insight into the physiological importance of Ada3, we established a conditional knockout mouse model and showed that loss of Ada3 led to embryonic lethality at an early stage of development. Using the derived Ada3lox/lox mouse embryonic fibroblast (MEF) cell lines we show that Ada3 deletion causes defects in histone acetylation. Also we show that Ada3 enhances catalytic activity of p300 HAT. We further showed that Ada3 plays an important role in cell proliferation; depletion of Ada3 from cells caused cell lethality. This proliferation defect was reversed by introduction of human Ada3 in Ada3 null MEFs. Ada3 null MEFs also showed delay in transition from G0-G1 phase of the cell cycle to the S phase. These cells also manifested decreased hyperphosphorylation of Retinoblastoma protein (Rb); an increased protein half life of CDK inhibitor p27Kip1 and decrease in Cdk2 kinase activity. The increase in p27 protein was a result of decreased Skp2 protein and mRNA levels which is a direct target of c-myc oncogene. We further show that mRNA levels of c-myc, a direct transcriptional target of Ada3 containing STAGA HAT complex, are reduced on deletion of Ada3. These data suggest an Ada3-myc-skp2-p27 pathway that controls mammalian cell cycle. Taken together, our data suggests an essential role of Ada3 in embryonic development and cell cycle progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3062. doi:1538-7445.AM2012-3062