Baniulyte Gabriele, Durham Serene A, Merchant Lauren E, Sammons Morgan A
Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA.
bioRxiv. 2023 Jun 5:2023.03.15.532778. doi: 10.1101/2023.03.15.532778.
The master tumor suppressor p53 regulates multiple cell fate decisions, like 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 anti-cancer 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 pro-apoptotic 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.
主要肿瘤抑制因子p53通过对广泛基因网络的转录控制来调节多种细胞命运决定，如细胞周期停滞和凋亡。p53网络功能障碍在癌症中很常见，通常是通过使p53或该通路其他成员失活的突变。通过恢复p53活性诱导肿瘤特异性细胞死亡且无脱靶效应，已在该领域引起了极大关注。在本研究中，我们探索了一种假定的抗癌策略背后的基因调控机制，该策略涉及刺激非p53依赖性综合应激反应（ISR）。我们的数据表明，p53和ISR通路汇聚以独立调节共同的代谢和促凋亡基因。我们研究了由p53和控制这种共同调节的ISR效应因子ATF4结合的多个基因调控元件的结构。我们鉴定了控制这些共享的p53和ATF4靶基因基础和应激诱导调节的其他关键转录因子。因此，我们的结果为众多抗肿瘤疗法所靶向的基因调控网络和转录因子提供了重要的新分子和遗传学见解。
