Shared gene targets of the ATF4 and p53 transcriptional networks.
Shared gene targets of the ATF4 and p53 transcriptional networks.
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ATF4 和 p53 转录网络的共享基因靶标。
DOI：
10.1101/2023.03.15.532778
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sammons,MorganA
中科院分区：
文献类型：
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作者：
Baniulyte,Gabriele;Durham,SereneA;Merchant,LaurenE;Sammons,MorganA
主肿瘤抑制因子p53通过广泛的基因网络的转录控制来调节多个细胞命运决定，例如细胞周期停滞和凋亡。p53网络的功能障碍在癌症中很常见，通常是通过使p53或该途径的其他成员发生突变。通过恢复p53活性而没有脱靶效应来诱导肿瘤特异性细胞死亡已经在该领域中获得了显著的兴趣。在这项研究中，我们探讨了一个假定的抗癌策略，涉及刺激p53独立的综合应激反应（ISR）的基因调控机制。我们的数据表明p53和ISR途径会聚以独立调节常见的代谢和促凋亡基因。我们研究了由p53和ISR效应器ATF4控制的多个基因调控元件的结构。我们确定了额外的关键转录因子，控制这些共享的p53和ATF 4靶基因的基础和应激诱导的调节。因此，我们的研究结果为基因调控网络和转录因子提供了重要的新的分子和遗传学见解，这些基因调控网络和转录因子是许多抗肿瘤治疗的靶点。
The master tumor suppressor p53 regulates multiple cell fate decisions, such as cell cycle arrest and apoptosis, via transcriptional control of a broad gene network. Dysfunction in the p53 network is common in cancer, often through mutations that inactivate p53 or other members of the pathway. Induction of tumor-specific cell death by restoration of p53 activity without off-target effects has gained significant interest in the field. In this study, we explore the gene regulatory mechanisms underlying a putative anticancer strategy involving stimulation of the p53-independent integrated stress response (ISR). Our data demonstrate the p53 and ISR pathways converge to independently regulate common metabolic and proapoptotic genes. We investigated the architecture of multiple gene regulatory elements bound by p53 and the ISR effector ATF4 controlling this shared regulation. We identified additional key transcription factors that control basal and stress-induced regulation of these shared p53 and ATF4 target genes. Thus, our results provide significant new molecular and genetic insight into gene regulatory networks and transcription factors that are the target of numerous antitumor therapies.