Mice Are Not Humans: The Case of p53

Fischer, Martin

doi:10.1016/j.trecan.2020.08.007

Cited by 30 publications

(23 citation statements)

References 15 publications

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“…An increasing number of available high-throughput datasets enabled us to generate ranked lists of p63-regulated genes and p63-bound DNA sites that together reveal high-probability direct p63 target genes regulated by p63 across cells of multiple origins. Because p63 target genes, very much like p53 target genes ( Fischer, 2020 ; Fischer, 2019 ), differ substantially between mouse and human ( Sethi et al, 2017 ), many p63 target genes initially described in mouse could not be confirmed to be p63-regulated in this study using human data. Given that p63-binding sites are frequently associated with enhancer regions and enhancer identity, we have integrated enhancer:gene associations to identify target genes that are regulated by p63 through direct binding to associated enhancers.…”

Section: Discussionmentioning

confidence: 72%

“…Also, the frequent binding of p63 to enhancers ( Kouwenhoven et al, 2015a ; Lin-Shiao et al, 2019 ; Lin-Shiao et al, 2018 ; Qu et al, 2018 ; Somerville et al, 2018 ) and the difficulty to associate such enhancers with target gene regulation adds another level of complexity to the quest of describing the GRN. To overcome these limitations, we utilize a recently developed meta-analysis approach ( Fischer et al, 2016a ), which helped us to dissect the GRNs of the mouse and human orthologue of p53 ( Fischer, 2020 ; Fischer, 2019 ). The analysis rests upon a ranking of potential p63 target genes based on the number of datasets supporting a p63-dependent regulation.…”

Section: Introductionmentioning

confidence: 99%

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Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

Riege

Kretzmer

Sahm

et al. 2020

eLife

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The transcription factor p53 is the best-known tumor suppressor, but its sibling p63 is a master regulator of epidermis development and a key oncogenic driver in squamous cell carcinomas (SCC). Despite multiple gene expression studies becoming available, the limited overlap of reported p63-dependent genes has made it difficult to decipher the p63 gene regulatory network. Particularly, analyses of p63 response elements differed substantially among the studies. To address this intricate data situation, we provide an integrated resource that enables assessing the p63-dependent regulation of any human gene of interest. We use a novel iterative de novo motif search approach in conjunction with extensive ChIP-seq data to achieve a precise global distinction between p53 and p63 binding sites, recognition motifs, and potential co-factors. We integrate these data with enhancer:gene associations to predict p63 target genes and identify those that are commonly de-regulated in SCC representing candidates for prognosis and therapeutic interventions.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

Riege

Kretzmer

Sahm

et al. 2020

eLife

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“…For example, p53 regulates the largest subset of genes indirectly through its direct target gene CDKN1A , encoding cyclin-dependent kinase inhibitor p21 and reactivating DREAM and RB:E2F trans -repressor complexes to down-regulate cell cycle genes ( 23–27 ). Intriguingly, indirect down-regulation of cell cycle genes by p53 is well conserved, while direct p53 targets diverged substantially during evolution ( 28 , 29 ). Yet, complex cross-talks between signaling pathways impede the identification of indirect regulations.…”

Section: Introductionmentioning

confidence: 99%

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Coronel

Riege

Schwab

et al. 2021

Nucleic Acids Research

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Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

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“…Nonetheless, the canonical tumour suppressive functions of p53 are still heavily intertwined with its long-established role in activating apoptotic cell death. Whilst this involves transcriptional upregulation of direct activators of apoptosis-such as PUMA, An emerging concept is that high affinity p53REs are well conserved across species and are present at cell cycle arrest genes (e.g., CDKN1A/p21) whilst lower affinity, evolutionary divergent p53REs are found at pro-apoptotic genes (e.g., BAX/BAX) [30,31]. However, the underlying molecular mechanisms which dictate p53 binding at distinct p53REs remain poorly defined.…”

Section: P53-a Tumour Suppressive Transcription Factormentioning

confidence: 99%

Dying to Survive—The p53 Paradox

Lees

Sessler

McDade

2021

Cancers

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The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.

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Mice Are Not Humans: The Case of p53

Cited by 30 publications

References 15 publications

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Dying to Survive—The p53 Paradox

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