气候变化领域集成服务门户(CCPortal): The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs

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DOI	10.1073/pnas.2025539118
	The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs
	Tesfaye E.; Martinez-Terroba E.; Bendor J.; Winkler L.; Olivero C.; Chen K.; Feldser D.M.; Zamudio J.R.; Dimitrova N.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	LncRNA; P53; Senescence; Transcription; Tumor suppression
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238839
作者单位	Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, United States; Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, United States; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, United States
推荐引用方式 GB/T 7714	Tesfaye E.,Martinez-Terroba E.,Bendor J.,et al. The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs[J],2021,118(31).
APA	Tesfaye E..,Martinez-Terroba E..,Bendor J..,Winkler L..,Olivero C..,...&Dimitrova N..(2021).The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Tesfaye E.,et al."The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).