A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells

Tichon, Ailone; Gil, Noa; Lubelsky, Yoav; Solomon, Tal Havkin; Lemze, Doron; Itzkovitz, Shalev; Stern-Ginossar, Noam; Ulitsky, Igor

doi:10.1101/033423

Cited by 23 publications

(36 citation statements)

References 50 publications

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“…NORAD, a highly conserved lncRNA, has been reported to act as a negative regulator of Pumilio proteins, 17,18 the RNA-binding posttranscriptional repressors of the specific mRNAs, and it has also been implicated in tumor progression. In breast cancer cells, knockout of NORAD suppresses tumor cell growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…The positions of the molecular weight markers are shown on the right spectrometry. 17,18 Interestingly, this suggested that NORAD interacts with importin 7 and importin b1, both of which have been reported to be important for the nuclear import of phosphorylated Smads. [2][3][4] In particular, the results of co-immunoprecipitation assay showed that knockdown of NORAD partially inhibited interactions between Smad3 and importin b1 in TGF-b-treated A549 cells ( Figure 3C).…”

Section: Norad Is Important For Nuclear Transport Of the Transformimentioning

confidence: 94%

“…We then reanalyzed published data (GSE79804) involving human osteosarcoma U2OS cells. 18 The results of U2OS cells in which NORAD was overexpressed ( Figure S1A…”

Section: Chipmentioning

confidence: 99%

“…NORAD thus upregulates target transcripts of Pumilio proteins and plays a role in genomic stability. 17,18 In addition, NORAD is reported to be an oncogene, as its expression is associated with poor prognosis in breast and pancreatic cancer patients. 19,20 In pancreatic cancer cells, NORAD has been demonstrated to promote EMT and metastasis; however, the mechanisms underlying these events are not fully understood.…”

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confidence: 99%

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Long noncoding RNA NORAD regulates transforming growth factor‐β signaling and epithelial‐to‐mesenchymal transition‐like phenotype

et al. 2018

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Long noncoding RNAs are involved in a variety of cellular functions. In particular, an increasing number of studies have revealed the functions of long noncoding RNA in various cancers; however, their precise roles and mechanisms of action remain to be elucidated. NORAD, a cytoplasmic long noncoding RNA, is upregulated by irradiation and functions as a potential oncogenic factor by binding and inhibiting Pumilio proteins (PUM1/PUM2). Here, we show that NORAD upregulates transforming growth factor‐β (TGF‐β) signaling and regulates TGF‐β‐induced epithelial‐to‐mesenchymal transition (EMT)‐like phenotype, which is a critical step in the progression of lung adenocarcinoma, A549 cells. However, PUM1 does not appear to be involved in this process. We thus focused on importin β1 as a binding partner of NORAD and found that knockdown of NORAD partially inhibits the physical interaction of importin β1 with Smad3, inhibiting the nuclear accumulation of Smad complexes in response to TGF‐β. Our findings may provide a new mechanism underlying the function of NORAD in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Norad Is Important For Nuclear Transport Of the Transformimentioning

confidence: 94%

“…We then reanalyzed published data (GSE79804) involving human osteosarcoma U2OS cells. 18 The results of U2OS cells in which NORAD was overexpressed ( Figure S1A…”

Section: Chipmentioning

confidence: 99%

mentioning

confidence: 99%

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Long noncoding RNA NORAD regulates transforming growth factor‐β signaling and epithelial‐to‐mesenchymal transition‐like phenotype

et al. 2018

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“…The binding of FBF to ncRNA indicates that PUFs may target and control RNAs outside of the context of translational control. Of note, recent work in human cells demonstrates that a lincRNA can interact with PUM2 to modulate its RNA binding and target repression activities (Tichon et al 2015).…”

Section: Fbf Targetsmentioning

confidence: 99%

The PUF binding landscape in metazoan germ cells

Prasad

Porter

Kroll-Conner

et al. 2016

RNA

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PUF (Pumilio/FBF) proteins are RNA-binding proteins and conserved stem cell regulators. The Caenorhabditis elegans PUF proteins FBF-1 and FBF-2 (collectively FBF) regulate mRNAs in germ cells. Without FBF, adult germlines lose all stem cells. A major gap in our understanding of PUF proteins, including FBF, is a global view of their binding sites in their native context (i.e., their "binding landscape"). To understand the interactions underlying FBF function, we used iCLIP (individual-nucleotide resolution UV crosslinking and immunoprecipitation) to determine binding landscapes of C. elegans FBF-1 and FBF-2 in the germline tissue of intact animals. Multiple iCLIP peak-calling methods were compared to maximize identification of both established FBF binding sites and positive control target mRNAs in our iCLIP data. We discovered that FBF-1 and FBF-2 bind to RNAs through canonical as well as alternate motifs. We also analyzed crosslinking-induced mutations to map binding sites precisely and to identify key nucleotides that may be critical for FBF-RNA interactions. FBF-1 and FBF-2 can bind sites in the 5 ′ UTR, coding region, or 3 ′ UTR, but have a strong bias for the 3 ′ end of transcripts. FBF-1 and FBF-2 have strongly overlapping target profiles, including mRNAs and noncoding RNAs. From a statistically robust list of 1404 common FBF targets, 847 were previously unknown, 154 were related to cell cycle regulation, three were lincRNAs, and 335 were shared with the human PUF protein PUM2.

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A pan‐cancer atlas of cancer hallmark‐associated candidate driver lncRNAs

et al. 2018

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Substantial cancer genome sequencing efforts have discovered many important driver genes contributing to tumorigenesis. However, very little is known about the genetic alterations of long non‐coding RNAs (lncRNAs) in cancer. Thus, there is a need for systematic surveys of driver lncRNAs. Through integrative analysis of 5918 tumors across 11 cancer types, we revealed that lncRNAs have undergone dramatic genomic alterations, many of which are mutually exclusive with well‐known cancer genes. Using the hypothesis of functional redundancy of mutual exclusivity, we developed a computational framework to identify driver lncRNAs associated with different cancer hallmarks. Applying it to pan‐cancer data, we identified 378 candidate driver lncRNAs whose genomic features highly resemble the known cancer driver genes (e.g. high conservation and early replication). We further validated the candidate driver lncRNAs involved in ‘Tissue Invasion and Metastasis’ in lung adenocarcinoma and breast cancer, and also highlighted their potential roles in improving clinical outcomes. In summary, we have generated a comprehensive landscape of cancer candidate driver lncRNAs that could act as a starting point for future functional explorations, as well as the identification of biomarkers and lncRNA‐based target therapy.

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A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells

Cited by 23 publications

References 50 publications

Long noncoding RNA NORAD regulates transforming growth factor‐β signaling and epithelial‐to‐mesenchymal transition‐like phenotype

Long noncoding RNA NORAD regulates transforming growth factor‐β signaling and epithelial‐to‐mesenchymal transition‐like phenotype

The PUF binding landscape in metazoan germ cells

A pan‐cancer atlas of cancer hallmark‐associated candidate driver lncRNAs

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