The transcriptional repressor hDaxx potentiates p53-dependent apoptosis
The transcriptional repressor hDaxx potentiates p53-dependent apoptosis
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DOI：
10.1074/jbc.m310801200
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发表时间：
2004-11-12
影响因子：
4.8
通讯作者：
Del Sal, G
中科院分区：
文献类型：
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作者：
Gostissa, M;Morelli, M;Del Sal, G
P53及其同系物P73和P63是转录因子，在调节细胞周期停滞和细胞死亡过程中发挥重要作用。这些反应的类型和强度可能会因诱导刺激和整个细胞环境的不同而不同，人们认为这些反应依赖于特定的靶基因亚集的激活。P53家族成员的正确激活需要翻译后修饰的协调作用以及与几个辅助因子的相互作用。在这项研究中，我们证明了多功能蛋白hDaxx在体外和体内都与P53及其同系物相互作用，并调节它们的转录活性。此外，我们还发现，hDaxx参与了多种细胞凋亡途径，增加了对DNA损伤诱导的细胞死亡的敏感性，这一效应需要p53的存在。尽管hDaxx抑制依赖于p53的p21基因转录，但它不影响促凋亡基因的激活，因此通过影响细胞周期停滞和促凋亡p53靶点之间的平衡而起作用。因此，我们的结果强调了hDaxx在调节几种刺激下的凋亡阈值中的中心作用，并确认它是协调p53家族成员反应的一个可能的整合因子。
p53 and its homologues p73 and p63 are transcription factors that play an essential role in modulating cell cycle arrest and cell death in response to several environmental stresses. The type and intensity of these responses, which can be different depending on the inducing stimulus and on the overall cellular context, are believed to rely on the activation of defined subsets of target genes. The proper activation of p53 family members requires the coordinated action of post-translational modifications and interaction with several cofactors. In this study, we demonstrate that the multifunctional protein hDaxx interacts with p53 and its homologues, both in vitro and in vivo, and modulates their transcriptional activity. Moreover, we show that hDaxx, which has been implicated in several apoptotic pathways, increases the sensitivity to DNA damage-induced cell death and that this effect requires the presence of p53. Although hDaxx represses p53-dependent transcription of the p21 gene, it does not affect the activation of proapoptotic genes, and therefore acts by influencing the balance between cell cycle arrest and proapoptotic p53 targets. Our results therefore underline the central role of hDaxx in modulating the apoptotic threshold upon several stimuli and identify it as a possible integrating factor that coordinates the response of p53 family members.