Closest sequence finder program predicts offtarget drug binding in. Recent genomewide analyses and metaanalyses of genomewide datasets of p53 dnabinding and gene regulation show that p53 is a direct activator of a limited number of genes compared to the number of putative responseelements identified genomewide. Precise gene editing preserves hematopoietic stem cell. The umd tp53 mutation database includes the tp53 status of more than 80,400 tumors, individuals with germline mutations and cell lines. T 1 is the similar ratio for genes in our p53 target database. Global transcriptional program of p53 target genes during. Given the heterogeneity among studies, it is likely that consistent findings reveal true p53 target genes.
Recent evidence suggests that p53 may contribute to the regulation of cell invasion and. Through bioinformatics analysis of microarray data, compared with 287 p53 target genes whose data come from transcriptional regulatory element database tred 25, 26, we found 34 of these p53 target genes showed consequent changes in gene expression in stable cell line overexpressing meg3 tables 1 and 2 including 21 upregulated genes. In this study, we describe a novel p53 target gene, fuca1, which encodes a fucosidase. See detailed information on database contents in the users guide. Mutant p53 may activate target genes through the interaction of transcription factors or through histone modifications. All noncommercial software used in these studies was written in perl 5. Global analysis of p53regulated transcription identifies. The tolllike receptor gene family is integrated into. This study shows that tp53 activates a genetically robust transcriptional program with highly distributed tumor suppressive functions acting in diverse cellular. Histone deacetylase 5 is not a p53 target gene, but its. Stress 1 is able to induce a cellular environment where coactivators a and b are available. The transcriptional targets of p53 in apoptosis control.
How can i find target genes of a transcription factor with rna seq data. The p53 transcriptional program is regulated in a stimulusspecific fashion murrayzmijewski et al. Identification of p53target genes in danio rerio europe. As a control, mouse p53 cdna was also included in the list of target genes to monitor the efficiency of inhibitory oligo sequence selection as well as their ability to mediate ras transformation in functional assays that followed the synthesis and cloning of shrnas. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream. While the autophagy program is regulated predominantly by p53, the p53 family. In cell types a and b, both locus x and y exhibit similar amounts of bound p53, however, their transcriptional output differs. Furthermore, these data are not collected in relational databases accessible. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from highthroughput studies, and 346 target genes from individual.
Location of p53 binding loci around target genes and validation by gene expression. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. Thank you for sending your work entitled global analysis of p53 regulated transcription identifies its direct targets and unexpected regulatory mechanisms for consideration at elife. The p53 mutation database consists of a list of point mutations in the p53 gene of human tumors and cell lines, compiled from the published literature and made available through electronic media. How can i find target genes of a transcription factor. These changes have been found in a genetic condition called lifraumeni syndrome and in many types of cancer. Compared with 287 p53 target genes whose data come from transcriptional regulatory element database tred, we found 34 of these p53 target genes showed consequent changes in gene expression in.
Author summary among the most prominently studied regulators of gene function is the p53 tumor suppressor, which has many roles in human biology. Similar, although less confident, results could be obtained when the expression of genes was. Transcription factors tfs activate and repress target genes. Can you provide a link to download the tip software. The wide range of p53s biological effects can in part be explained by its activation of expression of a number of target genes including p21 waf1.
This r20 release compiles data on around 29900 somatic mutations, 9200 variants reported in snp databases, 1530 cancer familiesindividual carriers of a germline mutation, 2700 celllines, 900. Transcriptional regulation by p53 pubmed central pmc. Remarkably, 84% of these human genes were previously annotated as functionally validated or putative p53 targets in the p53famtag database 149 out of 178 table s5 and methods. Interestingly, the p53 target genes identified in this study appear to involve broad functional classes and multiple gene families that are related, directly or indirectly, to the p53 pathway in human.
The p53famtag database p53 family target genes was. A target genes are classified as conserved or turnover based on p53 binding sites to corresponding aligned regions in human and mouse genome. Dual regulation of p53 by the ribosome maturation factor. Long noncoding rna meg3 interacts with p53 protein and.
Jun 10, 2005 many of the p53 apoptotic targets are part of the basic apoptotic machinery and can clearly act independent of p53. Graphs displaying summary information of all variants in the database reading frame checker the readingframe checker generates a prediction of the effect of wholeexon changes. Through bioinformatics analysis of microarray data, compared with 287 p53 target genes whose data come from transcriptional regulatory element database tred 25, 26, we found 34 of these p53 target genes showed consequent changes in gene expression in stable cell line overexpressing meg3 tables 1 and 2 including 21 upregulated genes which. Mutations changes in the p53 gene may cause cancer cells to grow and spread in the body. Apr 10, 2019 our rigorous approach revealed a large p53 genomewide cistrome composed of 900 genes directly targeted by p53. This software was used for the creation and analysis of various mutation databases that have been described over the past few years. Vousden and prives 2009, whereby distinct subsets of p53 target genes are induced in response to different p53activating agents, likely allowing cells to tailor their response to different types of stress. Recently some impacts of p53 mutations have been characterized as gainoffunction, expanding the mechanisms by which mutant p53 is known to function in cancer. Ten genes including col17a1, crot, fam198b, greb1, lama3, micalcl, npy1r, slc27a2, sytl2, and tspan1 are identified as p53 target gene candidates from this screening. It is your responsibility to ensure that your use and exploitation of the data does not infringe the rights of such. Global analysis of p53regulated transcription identifies its direct.
Forkhead transcription factor foxf1 is a novel target gene. Activation of p53 by various types of cellular stresses induces the expression of different subsets of p53 target genes, which leads to a range of cellular outcomes from cell recovery to cell. Therefore, targeting the p53 responsive elements of these genes to dissect p53 dependent function from other functions is anticipated. It is your responsibility to ensure that your use and exploitation of the data does not infringe the rights of such third parties. Pmc free article laurentpuig p, beroud c, soussi t. Graphs displaying summary information of all variants in the database. This site still includes former features, such as tp53 history, tp53 information or the tp53 mutation database. Reading frame checker the readingframe checker generates a prediction of the effect of wholeexon changes.
The ratio between p53 target genes and nontarget genes in the human genome is therefore, equation 1 the fraction of p53 target genes included in the p53 target data base is defined as p, and the fraction of indirectly regulated and nonp53 regulated genes included in p53 target data base is q, such that p, q mar, 2017 survey of 346 target genes derived from 319 individual gene studies. Global transcriptional program of p53 target genes during the. Compared with 287 p53 target genes whose data come from transcriptional regulatory element database tred, we found 34 of these p53 target genes showed consequent changes in gene expression in stable cell line overexpressing meg3 tables tables1 1 and and2 2. A global map of p53 transcriptionfactor binding sites in the human genome. Transcriptional regulation of the p53 tumor suppressor. Reduction of viability correlated with increased and selective transcription of p53 target genes such as btg2, p21, puma, fas, tnf, and tnfrsf10b, which promote apoptosis and cell cycle arrest. Finally, analysis of a human hepatocellular carcinoma hcc database the cancer genome atlas tcgaliver hepatocellular carcinoma. Definition of p53 gene nci dictionary of cancer terms. Novel p53 target gene fuca1 encodes a fucosidase and. Dna microarrays identification of primary and secondary.
This domain is followed by the proline rich domain pxxp, whereby the motif pxxp is repeated p is a proline and x can be any amino acid. Genecards is a searchable, integrative database that provides comprehensive, userfriendly information on all annotated and predicted human genes. Autophagy is another cellular program that is triggered by cell stress and p53. The e3ubiquitin ligase mdm2, encoded by a p53 target gene, is the core repressor of p53 by mediating its proteasomal degradation, translational inhibition, and functional inactivation. Highactivity, or noncanonical p53 res predicted to be moderately active were mapped by our tools near the tss of genes that are not completely established or novel putative direct p53 target genes.
Sep 21, 2012 mutant p53 may activate target genes through the interaction of transcription factors or through histone modifications. Cdkn1a is a wellcharacterized p53 target gene encoding a cyclindependent kinase inhibitor kaeser and iggo, 2002. We previously attempted to identify p53 target genes by microarray expression and chip. Chromatin immunoprecipitation chip is a method commonly used to study these types of protein interactions. Previously, we sought to define the p53 network in terms of functionality, specifically the ability of target response element sequences res to support p53. Expression of p53 target genes in the early phase of long. One ofunknown p53 early transcripts was identified to be histone deacetylase5 hdac5. P53 activity can be modulated by different binding partners to induce differential transactivation of target genes and outcome. One of these genes encodes a cki protein called p21, which binds to g1scdk and scdk and inhibits their activities, thereby helping to block entry into s phase. In a recent study, we reported on a p53 target database, consisting of 4852 human genes that contain at least one p53 consensus binding sequence in their regulatory region wang et al. This database includes also novel mutations that target specifically tp53 isoforms beta and gamma. Our data, therefore, demonstrates that suppression of p53 target gene, btg2, can indeed sensitize cells to the acquisition of tumorigenic phenotype in the presence of functional p53, thus providing a missing link between p53.
More targets, more pathways and more clues for mutant p53. Egr1, p73, and p53 form a network with positive feedback loops, which respond to stress by the prolonged expression of the p53 family of genes, which results in efficient apoptosis. This study presents a p53 target screening based on human breast cell lines and breast cancer tissues. The p53 recognition motif is a decamer sequence to which the homotetrameric form of p53 protein binds table 1.
A fishspecific transposable element shapes the repertoire of. Strikingly, 20 novel p53 target gene candidates are associated with the regulation of cell motility and adhesion. Rna sequencing analysis shows that only a subset of p53bound genes is. Aug 10, 2016 here, we have taken p53 as a model transcription factor and using the usp programme predict unique p53 binding sequences in the p53 target genes implicated in breast cancer.
Census and evaluation of p53 target genes oncogene. In order to generate a list of target genes that may be activated through this mechanism, chip sequencing may be used. For example, the large number of mutations in lung cancer, either sclc or nsclc, can be useful in statistical studies of various histological subgroups. In mammalian cells, for example, dna damage leads to the activation of the gene regulatory protein p53, which stimulates the transcription of several genes. Our in silico approach is a powerful method for identification of functional p53 binding sites and p53 target genes that are conserved among humans and other organisms and for further understanding the function of p53 in tumorigenesis. A proportion that should be compared to the about 1% of human protein coding genes gencode v12. Global genomic profiling reveals an extensive p53regulated. Starting from the nterminus, there are first the aminoterminal transactivation domains tad 1, tad 2, which are needed to induce a subset of p53 target genes. May 27, 2011 transcript expression of p53 target genes in metastatic melanoma.
The p53 target gene dram1 encodes a lysosomal membrane. To determine genes involved in the p53 signalling pathway that were altered in metastatic melanoma, whole genome bead arrays were used to analyse gene expression patterns in 82 metastatic melanomas compared to 8 diploid melanocyte strains, which were used as a normal control. The transcriptional networks influenced by the p53 tumor suppressor are. As a transcription factor, p53 regulates the expression of genes. A global map of p53 transcriptionfactor binding sites in the.
Analyses of p53 target genes in the human genome by. In the survey presented here, a total set of 3661 direct p53 target genes is identified that comprise 3509 potential targets from highthroughput studies, and 346 target genes from. A global map of p53 transcriptionfactor binding sites in. This section contains data that may be subject to thirdparty constraints.
However, in response to stress, egr1 displays a remarkable functional similarity to p53 and p73 8184. Two different outpouts from the database are currently available. Tumor suppressor p53 plays a key role in induction of both. Through bioinformatics analysis of microarray data, compared with 287 p53 target genes whose data come from transcriptional regulatory element database tred 25, 26, we found 34 of these p53 target genes showed consequent changes in gene expression in stable cell line overexpressing meg3 tables tables1 1 and and2 2 including 21 up. As mentioned above, the differential regulation of p53 target genes observed in vivo could be explained by a myriad of factors, including p53. Pdf p53, skp2, and dkk3 as mycn target genes and their. There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. This database is the first and unique integrated resource of human direct p53 family target genes.
We report here an analysis of its direct transcriptional program using global. Tp53tg5 tp53tg5 by screening a human cosmid library with a fragment containing a p53 responsive element, followed by screening a testis cdna library, isaka et al. Transcriptional regulation of the p53 tumor suppressor gene. A database resource of human p53, p63 and p73 direct target genes combining in silico prediction and microarray data. Mar 21, 2016 the tumor suppressor p53 functions by inducing the transcription of a collection of target genes. The huge increase in p53 mutations since our last report enables a more precise analysis. In a recent study, we reported on a p53 target database, consisting of 4852 human genes that contain at least one p53 consensus binding. In examining the rates of expression of p53 target genes and the rates of entry into apoptosis, evidence has accumulated that indicates that this induction occurs to provide sufficient p53 mrna to ensure a rapid response to dna damage before exiting sphase. Gse56 significantly mitigated the p53 dependent transcriptional response, as measured by lower upregulation of p53 target genes upon editing, including p21 figure 5a. However, it was not clear which p53 target genes were involved in this cellular process. A study in three cancer cell lines of different origin showed that p53 activated by the mdm2 inhibitor nutlin induces transcription of around one hundred target genes andrysik et al. The size of each word indicates its frequency of overlap across data sets. Collectively, our analysis identified 7 novel p53 target genes. Espinosa1 howard hughes medical institute, department of molecular, cellular, and developmental biology, the university of colorado at boulder, boulder, colorado 80309, usa p53 is a pleiotropic transcription factor driving a flex.
The p53 target database could not only be used to delineate p53 target genes, but also could assist to identify other signaling pathways that are potentially connected to the p53 pathway. Oncotarget identification of a novel p53 target, col17a1. Identification of a core tp53 transcriptional program with highly. The p53famtag database p53 family target genes was developed to organize all the data produced by computational analysis and by microarray experiments. Comparative genome analysis identifies the vitamin d receptor. We tested a hypothesis that hdac5 is a p53 downstream target gene that on induction by p53 inactivates p53 by removal of acetyl group in p53 molecule, thus functioning as an autoregulatory negative feedback loop in analogue.
Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment andor cellspecific, demonstrating new functions for p53 in cell biology. The new tp53 website has been launched with a novel design, updated information and improved readability. This site still includes former features, such as tp53 history, tp53 information or the tp53 mutation database, but these features have been updated to take into account the most recent developments in this exciting field. In cell types a and b, both locus x and y exhibit similar amounts of bound p53, however, their transcriptional. The p53 tumor suppressor induces the transcription of genes that negatively regulate progression of the cell cycle in response to dna damage or other cellular stressors and thus participates in maintaining genome stability. Identifying the target genes of suppressor of gamma response. Chip sequencing to identify p53 targets springerlink. P53 in human melanoma fails to regulate target genes. Our finding that abca1 is a bona fide p53 target gene is. This r package provides easy access to query a particular tf and find its targets in humans.
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