The dichotomy of p53 regulation by noncoding RNAs

Deng, Qipan; Becker, Lindsey; Ma, Xiaodong; Zhong, Xiaoming; Young, Ken H.; Ramos, Kenneth S.; Li, Yong

doi:10.1093/jmcb/mju017

Cited by 13 publications

(14 citation statements)

References 73 publications

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“…This suggests that neural development is a complex process that integrates proliferation, differentiation and programmed cell death or autophagy. Our findings that depletion of MALAT1 leads to activation of p53 are consistent with several previous studies [23,30] and might contribute to cell death in Malat1 knockout cells. In response to stress stimuli such as serum withdrawal or RA treatment, cells might face critical decision making in terms of differentiation or cell death during the transition, presumably determined by different external signals and/or internal signal transduction whose nature yet remains to be elucidated.…”

Section: Discussionsupporting

confidence: 93%

Long non‐coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells

Chen

Feng

Zhu

et al. 2016

J Cellular Molecular Medi

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Accumulating evidence suggests that long non‐coding RNAs (lncRNAs) are playing critical roles in neurogenesis, yet the underlying molecular mechanisms remain largely elusive. Neurite outgrowth is an early step in neuronal differentiation and regeneration. Using in vitro differentiation of neuroblastoma‐derived Neuro‐2a (N2a) cell as a model, we performed expression profiling to identify lncRNAs putatively relevant for neurite outgrowth. We identified that Metastasis‐associated lung adenocarcinoma transcript 1 (Malat1) was one of the most significantly up‐regulated lncRNAs during N2a cell differentiation. Malat1 knockdown resulted in defects in neurite outgrowth as well as enhanced cell death. To pinpoint signalling pathways perturbed by Malat1 depletion, we then performed a reporter‐based screening to examine the activities of 50 signalling pathways in Malat1 knockdown cells. We found that Malat1 knockdown resulted in conspicuous inhibition of Mitogen‐Activated Protein Kinase (MAPK) signaling pathway as well as abnormal activation of Peroxisome proliferator‐activated receptor (PPAR) and P53 signalling pathway. Inhibition of ERK/MAPK pathway with PD98059 potently blocked N2a cell neurite outgrowth, whereas phorbol 12‐myristate 13‐acetate‐induced ERK activation rescued defects in neurite outgrowth and cell death induced by Malat1 depletion. Together, our results established a critical role of Malat1 in the early step of neuronal differentiation through activating ERK/MAPK signalling pathway.

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Section: Discussionsupporting

confidence: 93%

Long non‐coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells

Chen

Feng

Zhu

et al. 2016

J Cellular Molecular Medi

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“…We showed previously that following cisplatin treatment, P53 may trigger apoptotic events in renal tubular cells via the regulation of pro-apoptotic genes, such as PUMA-␣ (29). Recent research has further suggested that P53 may also regulate a number of non-coding genes, including microRNAs and long noncoding RNAs (30,31). Several P53-microRNA signaling axis have also been described (32-34) and, in experimental models of cisplatin nephrotoxicity, we demonstrated activa- tion of the P53-miR-34a axis for renal cell survival (16).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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Edited by Joel GottesfeldNephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatininduced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatininduced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One upregulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-B attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-B in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1␤) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1␤ protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-B collaboratively induce miR-375 expression, which, in turn, represses HNF-1␤ activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

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“…Th e kinetics of P53-activating target genes changes through stimulus-and promoter-specifi c enrollment of transcription induction ingredients and polymerase II enzymes (17)(18)(19)(20). However, evidence based on genome-wide profi ling does not support the promoter-specifi c actions of the protein, thus suggesting an unsophisticated p53 binding (12).…”

Section: Introductionmentioning

confidence: 99%

“…Non-coding RNAs (ncRNAs) comprise a class of sequences that are able to regulate gene expression without undergoing translational processes (20).…”

Section: Introductionmentioning

confidence: 99%

New insights into the role of non-coding RNAs as transcriptional targets of p53

Cătană¹,

Gulei²,

Berindan‐Neagoe³

2017

Mol.Life

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undergoes programmed cell death (6). Th e main role of p53 as a carcinogenic inhibitor consists in the regulation at the transcriptional level of the target genes that control various cellular processes including programmed cell death, DNA repair mechanisms, autophagy, metabolism, cell cycle control and thus genetic integrity (7-10). Th e elements targeted by p53, a cancer suppressor interacting with numerous target genes, were presented through meta-analysis statistics, which showed that the target genes characterized by high confi dence are involved in numerous feedback loops at cellular level such as cell cycle arrest, metabolism, and mRNA translation. At the same time, a series of mechanisms were associated with the modulatory aspects of gene control in response to p53 (11-13). To our knowledge, research studies revealed that p53 can act as a catalyst of transcription. Moreover, gene down-regulation by p53 is indirect and Abstract P53 classifies as one of the main tumor suppressor gene and the identification of its direct transcriptional targets such as certain non-coding RNAs (ncRNAs) is important for understanding the development and progression of cancer. Multiple ncRNAs are targeting p53 and are involved in many cellular processes such as cell cycle arrest, metabolism, apoptosis, autophagy and feedback mechanisms. Also, various ncRNAs were found to modulate p53-dependent gene regulation. These include microRNAs such as miR-660, miR-486, miR-34 and lncRNAs such as nuclear enriched abundant transcript 1 (NEAT1), which contribute to the tumor-suppressor function of the p53 protein. Long intergenic non-coding RNA, LincRNA-p21, has been proclaimed to promote apoptosis while other p53-regulated lncRNAs including PANDA and Pint antagonize p53 activity by limiting the activation of proapoptotic genes. Taking into account the activity of the proapoptotic transcription factor p53, new conclusions point to a new concept of cellular quality control since ncRNAs-based deregulation in cancer functions in the absence of p53 coding sequence mutations.

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The dichotomy of p53 regulation by noncoding RNAs

Cited by 13 publications

References 73 publications

Long non‐coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells

Long non‐coding RNA Malat1 promotes neurite outgrowth through activation of ERK/MAPK signalling pathway in N2a cells

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

New insights into the role of non-coding RNAs as transcriptional targets of p53

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