Global Approaches in Studying RNA-Binding Protein Interaction Networks

Sternburg, Erin L.; Karginov, Fedor V.

doi:10.1016/j.tibs.2020.03.005

Cited by 40 publications

(25 citation statements)

References 95 publications

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“…Further Investigation of the Prognostic Effects and Dysregulation of RBPs of KPNA2, GRB2, and NRAS in HCC RBP binding at specific target sites could impact the expression of functionally coordinated sets of mRNAs and regulate their function in the cell (Sternburg and Karginov, 2020). Here, through The Encyclopedia of RNA Interactomes (ENCORI), 4 the RBPs of KPNA2 and its correlated BCR signaling pathway genes (GRB2 and NRAS) were also investigated.…”

Section: Exploration Of the Potential Roles Of Kpna2 Grb2 And Nras mentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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Karyopherin α2 (KPNA2) was reported to be overexpressed and have unfavorable prognostic effects in many malignancies including hepatocellular carcinoma (HCC). Although its contributions to inflammatory response were reported in many studies, its specific associations with immune infiltrations and immune pathways during cancer progression were unclear. Here, we aimed to identify new markers for HCC diagnosis and prognosis through KPNA2-associated immune analyses. RNA-seq expression data of HCC datasets were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. The gene expressions were counts per million normalized. The infiltrations of 24 kinds of immune cells in the samples were evaluated with ImmuCellAI (Immune Cell Abundance Identifier). The Spearman correlations of the immune infiltrations with KPNA2 expression were investigated, and the specific positive correlation of B-cell infiltration with KPNA2 expression in HCC tumors was identified. Fifteen genes in KEGG (Kyoto Encyclopedia of Genes and Genomes) B-cell receptor signaling pathway presented significant correlations with KPNA2 expression in HCC. Among them, GRB2 and NRAS were indicated to be independent unfavorable prognostic factors for HCC overall survival. Clinical Proteomic Tumor Analysis Consortium HCC dataset was investigated to validate the results at protein level. The upregulation and unfavorable prognostic effects of KPNA2 and GRB2 were confirmed, whereas, unlike its mRNA form, NRAS protein was presented to be downregulated and have favorable prognostic effects. Through receiver operating characteristic curve analysis, the diagnostic potential of the three proteins was shown. The RNA-binding proteins (RBPs) of KPNA2, NRAS, and GRB2, downloaded via The Encyclopedia of RNA Interactomes, were investigated for their clinical significance in HCC at protein level. An eight-RBP signature with independent prognostic value and dysregulations in HCC was identified. All the RBPs were significantly correlated with MKI67 expression and at least one of KPNA2, GRB2, and NRAS at protein level in HCC, indicating Zhang et al. KPNA2-Associated Immune Analyses in HCC Frontiers in Genetics | www.frontiersin.org 2 October 2020 | Volume 11 | Article 593273 their roles in HCC progression and the regulation of the three proteins. We concluded that KPNA2, GRB2, NRAS, and their RBPs might have coordinating roles in HCC immunoregulation and progression. They might be new markers for HCC diagnosis and prognosis predication and new targets for HCC immunotherapy.

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Section: Exploration Of the Potential Roles Of Kpna2 Grb2 And Nras mentioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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“…Expanding beyond this traditional target-specific strategy, recent developments in high throughput technologies (discussed below) have provided the ability to dissect the intricate relationships between translatome remodelers and their target mRNAs from a systems-level perspective (Achsel & Bagni, 2016;Ho, Balukoff, et al, 2020). This unbiased approach has revealed key principles of post-transcriptional regulation, including the fresh insight that in response to different stresses, translatome remodelers are dynamically repurposed and reorganized into unique networks, each targeting a distinct but overlapping selection of mRNAs to fully activate adaptive cellular pathways (Hogan et al, 2008;Mukherjee et al, 2019;Quattrone & Dassi, 2019;Sternburg & Karginov, 2020). For instance, a recent analysis of ENCODE datasets revealed RBP network rewiring during oncogenesis, including the activation of SUB1, which acts synergistically with the transcription factor MYC to enhance target protein expression through mRNA stabilization and increased transcription/mRNA synthesis, respectively (Zhang et al, 2020).…”

Section: High-throughput Strategies Reveal Systems-level Principles Of Translatome Remodelingmentioning

confidence: 99%

Translational remodeling by RNA‐binding proteins and noncoding RNAs

Man

Schatz

et al. 2021

WIREs RNA

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Responsible for generating the proteome that controls phenotype, translation is the ultimate convergence point for myriad upstream signals that influence gene expression. System-wide adaptive translational reprogramming has recently emerged as a pillar of cellular adaptation. As classic regulators of mRNA stability and translation efficiency, foundational studies established the concept of collaboration and competition between RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) on individual mRNAs. Fresh conceptual innovations now highlight stress-activated, evolutionarily conserved RBP networks and ncRNAs that increase the translation efficiency of populations of transcripts encoding proteins that participate in a common cellular process. The discovery of post-transcriptional functions for long noncoding RNAs (lncRNAs) was particularly intriguing given their cell-type-specificity and historical definition as nuclear-functioning epigenetic regulators. The convergence of RBPs, lncRNAs, and microRNAs on functionally related mRNAs to enable adaptive protein synthesis is a newer biological paradigm that highlights their role as "translatome (protein output) remodelers" and reinvigorates the paradigm of "RNA operons." Together, these concepts modernize our understanding of cellular stress adaptation and strategies for therapeutic development.

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“…To this end, RNA-binding proteins (RBPs) tag and group functionally related messenger RNAs (mRNAs) into RNA regulons (Keene, 2007;Shi & Barna, 2015;Van Nostrand et al, 2020) ensuring that proteins involved in a specific pathway are translated in a highly coordinated fashion. mRNAs, regulatory RNAs [micro-RNAs (miRNAs); long non-coding RNAs (lncRNAs)] and RBPs hierarchically engage in a spectrum of high-order interactions on specific mRNAs and it is the combination of all these elements that determine the fate of the targeted mRNAs (Sternburg & Karginov, 2020). Accordingly, even a slight alteration in the expression and/or activity of a single RBP can profoundly affect the pathway(s) controlled by its bound mRNAs.…”

Section: Introductionmentioning

confidence: 99%

The Staufen1‐dependent cell cycle regulon or how a misregulated RNA‐binding protein leads to cancer

Bonnet-Magnaval

DesGroseillers

2021

Biological Reviews

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In recent years, an increasing number of reports have linked the RNA-binding protein Staufen1 (STAU1) to the control of cell decision making. In non-transformed cells, STAU1 balances the expression of messenger RNA (mRNA) regulons that regulate differentiation and well-ordered cell division. Misregulation of STAU1 expression and/or functions changes the fragile balance in the expression of pro-and anti-proliferative and apoptotic genes and favours a novel equilibrium that supports cell proliferation and cancer development. The misregulation of STAU1 functions causes multiple coordinated modest effects in the post-transcriptional regulation of many RNA targets that code for cell cycle regulators, leading to dramatic consequences at the cellular level. The new tumorigenic equilibrium in STAU1-mediated gene regulation observed in cancer cells can be further altered by a slight increase in STAU1 expression that favours expression of pro-apoptotic genes and cell death. The STAU1-dependent cell cycle regulon is a good model to study how abnormal expression of an RNA-binding protein promotes cell growth and provides an advantageous selection of malignant cells in the first step of cancer development.

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Global Approaches in Studying RNA-Binding Protein Interaction Networks

Cited by 40 publications

References 95 publications

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Translational remodeling by RNA‐binding proteins and noncoding RNAs

The Staufen1‐dependent cell cycle regulon or how a misregulated RNA‐binding protein leads to cancer

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