Expanding the p53 regulatory network: LncRNAs take up the challenge

Grossi, E; Sánchez, Yolanda; Huarte, Maite

doi:10.1016/j.bbagrm.2015.07.011

Cited by 73 publications

(71 citation statements)

References 126 publications

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“…The most striking finding was that the TP53 target gene and CDK inhibitor p21 is critical to TP53-mediated transcriptional downregulation in general (Figure 3). These results challenge gene regulatory models that do not incorporate p21 in mediating TP53-dependent transcriptional downregulation, such as E2F7 (7), multiple microRNAs (73) and long non-coding RNAs (74). Our results suggest that the group of CC genes is primarily and generally regulated through the TP53-p21-DREAM (32) and TP53-p21-RB/E2F (28,29) pathways across cell types and treatments (Figure 6H).…”

Section: Discussionmentioning

confidence: 95%

Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks

et al. 2016

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Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.

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Section: Discussionmentioning

confidence: 95%

Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks

et al. 2016

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“…It has been increasingly recognized that lncRNA plays an important role in the regulation of the p53 response 18,19 . Therefore, identification and functional analysis of new p53-regulated lncRNA is of great importance to the understanding of p53 biology.…”

Section: Discussionmentioning

confidence: 99%

TRMP, a p53-inducible long noncoding RNA, regulates G1/S cell cycle progression by modulating IRES-dependent p27 translation

et al. 2018

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The tumor suppressor p53 plays a pivotal role in the protection against cancer. Increasing evidence suggests that long noncoding RNA (lncRNA) plays an important role in the regulation of the p53 pathway, however, the detailed mechanisms remain to be further elucidated. In this study, we report a new p53-inducible lncRNA that we termed TRMP (TP53-regulated modulator of p27). As a direct transcriptional target of p53, TRMP plays an unexpected pro-survival function. Knockdown of TRMP inhibits cell proliferation by inducing a G1 cell cycle arrest. Mechanistically, TRMP suppresses internal ribosomal entry site (IRES)-dependent translation of p27 by competing p27 mRNA for polypyrimidine tract-binding protein 1 (PTBP1) binding. Furthermore, TRMP is able to regulate cell proliferation, G1/S cell cycle progression, and tumor xenograft growth via the inhibition of p27. Taken together, these findings suggest lncRNA as a new layer to fine-tune the p53 response and reveal TRMP as an important downstream effector of p53 activity.

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“…Among those lncRNAs, 19 lncRNAs were specifically expressed in HPV+ and TP53 wild type tumors, suggesting that these lncRNAs are potential key molecules and that their study may provide novel insights into the mechanism of HPV-associated HNSCC oncogenesis. Recently, a growing number of studies have demonstrated that lncRNAs indeed act as functional components of the p53 pathway [56]. For example, tumor suppressive lncRNA, MEG3 directly interacts with p53, and activates several p53-dependent gene transcripts [57].…”

Section: Discussionmentioning

confidence: 99%

Unraveling the oral cancer lncRNAome: Identification of novel lncRNAs associated with malignant progression and HPV infection

2016

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Objectives The role of long non-coding RNA (lncRNA) expression in human head and neck squamous cell carcinoma (HNSCC) is still poorly understood. In this study, we aimed at establishing the onco-lncRNAome profiling of HNSCC and to identify lncRNAs correlating with prognosis and patient survival. Materials and Methods The Atlas of Noncoding RNAs in Cancer (TANRIC) database was employed to retrieve the lncRNA expression information generated from The Cancer Genome Atlas (TCGA) HNSCC RNA-sequencing data. RNA-sequencing data from HNSCC cell lines were also considered for this study. Bioinformatics approaches, such as differential gene expression analysis, survival analysis, principal component analysis, and Co-LncRNA enrichment analysis were performed. Results Using TCGA HNSCC RNA-sequencing data from 426 HNSCC and 42 adjacent normal tissues, we found 728 lncRNA transcripts significantly and differentially expressed in HNSCC. Among the 728 lncRNAs, 55 lncRNAs were significantly associated with poor prognosis, such as overall survival and/or disease-free survival. Next, we found 140 lncRNA transcripts significantly and differentially expressed between Human Papilloma Virus (HPV) positive tumors and HPV negative tumors. Thirty lncRNA transcripts were differentially expressed between TP53 mutated and TP53 wild type tumors. Co-LncRNA analysis suggested that protein-coding genes that are co-expressed with these deregulated lncRNAs might be involved in cancer associated molecular events. With consideration of differential expression of lncRNAs in a HNSCC cell lines panel (n=22), we found several lncRNAs that may represent potential targets for diagnosis, therapy and prevention of HNSCC. Conclusion LncRNAs profiling could provide novel insights into the potential mechanisms of HNSCC oncogenesis.

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Expanding the p53 regulatory network: LncRNAs take up the challenge

Cited by 73 publications

References 126 publications

Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks

Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks

TRMP, a p53-inducible long noncoding RNA, regulates G1/S cell cycle progression by modulating IRES-dependent p27 translation

Unraveling the oral cancer lncRNAome: Identification of novel lncRNAs associated with malignant progression and HPV infection

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