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Long noncoding RNAs in the p53 network

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The tumor‐suppressor protein p53 is activated in response to numerous cellular stresses including DNA damage. p53 functions primarily as a sequence‐specific transcription factor that controls the expression of hundreds of protein‐coding genes and noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). While the role of protein‐coding genes and miRNAs in mediating the effects of p53 has been extensively studied, the physiological function and molecular mechanisms by which p53‐regulated lncRNAs act is beginning to be understood. In this review, we discuss recent studies on lncRNAs that are directly or indirectly regulated by p53 and how they contribute to the biological outcomes of p53 activation. WIREs RNA 2017, 8:e1410. doi: 10.1002/wrna.1410 This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease
Regulation of proliferation and survival by the p53‐regulated lncRNA PANDA. PANDA is a direct target of p53 and its expression is induced following p53 activation after DNA damage. In response DNA damage PANDA has a prosurvival function as it promotes cell survival and inhibits apoptosis. PANDA interacts with the NF‐YA and thus restricts the binding of NF‐YA to chromatin, limiting the activation of apoptotic genes. In proliferating cells, PANDA interacts with SAFA and recruit PRC2‐EZH2 and BMI1–PRC1 complexes that inhibit transcription of PANDA and prosenescence genes including p21. When the levels of PANDA decrease, its affinity to bind with NF‐YA is low and NF‐YA can now activate E2F and promote cell proliferation. PANDA acts in an autoregulatory loop with SAFA–BMI1–PRC1. In senescent cells, SAFA–PRC2‐EZH2 and SAFA–BMI1–PRC1 complexes disintegrate and expression of PANDA and p21 is upregulated. PANDA now blocks proliferation by decoying NF‐YA, which is also required for survival of senescent cells.
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Diverse functions of lincRNA‐p21 in nucleus and cytoplasm. (a) In response to DNA damage, p53 is upregulated and activates the transcription of coding as well as noncoding transcripts including lincRNA‐p21. LincRNA‐p21 functions in cis‐ as well as in trans. In cis it regulates the expression of its neighboring gene p21. It has proapoptotic function and can regulate gene expression in trans by interacting with RNA‐binding protein hnRNP‐K. (b) LincRNA‐p21 expression is induced during hypoxia. Under normal oxygen levels HIF‐1α binds to VHL and is polyubiquitinated by VHL, leading to its degradation via proteasome. During hypoxic conditions, HIF‐1α levels increase, which in turn increases the levels of lincRNA‐p21. LincRNA‐p21 can now bind to VHL and HIF‐1α, therefore disrupting VHL‐HIF‐1α interaction. Once this interaction in disrupted the levels of HIF‐1α accumulate, suggesting the existence of feedback loop between HIF‐1α and lincRNA‐p21. (c)LincRNA‐p21 regulates translation in the cytoplasm. When cytoplasmic HuR levels are high, it associates with lincRNA‐p21 and recruits let‐7/Ago2 to lincRNA‐p21 leading to its degradation and thus activates translation of select mRNAs. However, when the levels of HuR are low, lincRNA‐p21 levels accumulate and it can now inhibit translation.
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LncRNA‐mediated regulation of p53. MEG3 induces p53 protein levels resulting in cell cycle arrest and inhibition of cell proliferation and thus inhibit tumorigenesis. MEG3 downregulates MDM2 expression that can possibly activate p53. LncRNAs H19, RoR, and 7SL act in an autoregulatory loop with p53. MT1JP regulates p53 protein by associating with RNA‐binding protein TIAR.
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LncRNAs in the p53 network. DNA damage activates p53 and its downstream transcriptional targets including lncRNAs. The human and mouse orthologs of lncRNA PINT have contrasting functions. Human PINT has a tumor‐suppressor function, whereas mouse ortholog increases cell survival and proliferation. PR‐lncRNA1 and PR‐LncRNA10 have proapoptotic function and they inhibit cell survival and proliferation. The LncRNA TUG1 has diverse role in different cancer types. TUG1 can promote or inhibit cell proliferation and cell cycle progression depending on the tumor type. The LncRNA NORAD is not a direct transcriptional target of p53 and it interacts with PUMILIO proteins to maintain genomic stability.
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RNA in Disease and Development > RNA in Disease
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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