NeuroVascular Coordination Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Cancer Res. 2010 Jun 1;70(11):4422-32. doi: 10.1158/0008-5472.CAN-09-3258. Epub 2010 May 25.
The N-acetyltransferase arrest defective 1 (ARD1) is an important regulator of cell growth and differentiation that has emerged recently as a critical molecule in cancer progression. However, the regulation of the enzymatic and biological activities of human ARD1 (hARD1) in cancer is presently poorly understood. Here, we report that hARD1 undergoes autoacetylation and that this modification is essential for its functional activation. Using liquid chromatography-tandem mass spectrometry and site-directed mutational analyses, we identified K136 residue as an autoacetylation target site. K136R mutation abolished the ability of hARD1 to promote cancer cell growth in vitro and tumor xenograft growth in vivo. Mechanistic investigations revealed that hARD1 autoacetylation stimulated cyclin D1 expression through activation of the transcription factors beta-catenin and activator protein-1. Our results show that hARD1 autoacetylation is critical for its activation and its ability to stimulate cancer cell proliferation and tumorigenesis.
N-乙酰基转移酶缺陷 1 (ARD1) 是细胞生长和分化的重要调节剂，最近已成为癌症进展中的关键分子。然而，目前对于 ARD1 在癌症中的酶和生物学活性的调节知之甚少。在这里，我们报告 hARD1 发生自身乙酰化，并且这种修饰对于其功能激活是必需的。通过液相色谱-串联质谱和定点突变分析，我们确定 K136 残基是自身乙酰化的靶位。K136R 突变消除了 hARD1 在体外促进癌细胞生长和体内肿瘤异种移植生长的能力。机制研究表明，hARD1 自身乙酰化通过激活转录因子β-catenin 和激活蛋白-1 刺激细胞周期蛋白 D1 的表达。我们的结果表明，hARD1 自身乙酰化对于其激活及其刺激癌细胞增殖和肿瘤发生的能力至关重要。
