TP53 活性通过乙酰化调节
中文名称
通路描述
TP53 转录活性通过其赖氨酸残基的乙酰化得到正调节。BRD7 结合 TP53，并由乙酰转移酶 EP300(p300)促进 TP53 赖氨酸残基 K382 的乙酰化。K382 的乙酰化增强了 TP53 与靶启动子（包括 CDKN1A(p21)、MDM2、SERPINE1、TIGAR、TNFRSF10C 和 NDRG1）的结合。KAT6A 在 PML 存在下，也在 K382 处乙酰化 TP53，并额外乙酰化 TP53 的 K120。KAT6A 介导的乙酰化增加了 TP53 对 CDKN1A 的转录激活作用（Rokudai et al. 2013）。NuRD 复合物（包含结合 TP53 的 MTA2 亚基）的乙酰化作用可以逆转 K382 的乙酰化，从而抑制 TP53 的转录活性（Luo et al. 2000）。MYST 家族乙酰转移酶 KAT8(hMOF) 和 KAT5(TIP60) 对 TP53 DNA 结合域中赖氨酸 K120 的乙酰化可以调节细胞周期停滞与凋亡之间的决定（Sykes et al. 2006, Tang et al. 2006）。具有乙酰化缺陷的敲入突变小鼠研究表明，p53 DNA 结合域中的赖氨酸乙酰化部分通过解耦基因靶标的转录激活和转录抑制起作用，同时保留调节能量代谢和产生活性氧（ROS）的能力，并影响铁死亡（Li et al. 2012, Jiang et al. 2015）。
英文描述
Regulation of TP53 Activity through Acetylation Transcriptional activity of TP53 is positively regulated by acetylation of several of its lysine residues. BRD7 binds TP53 and promotes acetylation of TP53 lysine residue K382 by acetyltransferase EP300 (p300). Acetylation of K382 enhances TP53 binding to target promoters, including CDKN1A (p21), MDM2, SERPINE1, TIGAR, TNFRSF10C and NDRG1 (Bensaad et al. 2010, Burrows et al. 2010. Drost et al. 2010). The histone acetyltransferase KAT6A, in the presence of PML, also acetylates TP53 at K382, and, in addition, acetylates K120 of TP53. KAT6A-mediated acetylation increases transcriptional activation of CDKN1A by TP53 (Rokudai et al. 2013). Acetylation of K382 can be reversed by the action of the NuRD complex, containing the TP53-binding MTA2 subunit, resulting in inhibition of TP53 transcriptional activity (Luo et al. 2000). Acetylation of lysine K120 in the DNA binding domain of TP53 by the MYST family acetyltransferases KAT8 (hMOF) and KAT5 (TIP60) can modulate the decision between cell cycle arrest and apoptosis (Sykes et al. 2006, Tang et al. 2006). Studies with acetylation-defective knock-in mutant mice indicate that lysine acetylation in the p53 DNA binding domain acts in part by uncoupling transactivation and transrepression of gene targets, while retaining ability to modulate energy metabolism and production of reactive oxygen species (ROS) and influencing ferroptosis (Li et al. 2012, Jiang et al. 2015).
所含基因
23 个基因