The emerging roles of hnRNPK

Wang, Ziyi; Qiu, Heng; He, Jianbo; Liu, Langxia; Wang, Xue; Fox, Archa; Tickner, Jennifer; Xu, Jiake

doi:10.1002/jcp.29186

Cited by 102 publications

(102 citation statements)

References 110 publications

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“…Two ribonucleoproteins that have been associated with apoptosis were downregulated at 8 h, including heterogeneous nuclear ribonucleoproteins A2/B1 (reduced ratios of −1.17 and −1.15 in two spots) and heterogeneous nuclear ribonucleoprotein K (hnRNPK: reduced ratio of −1.36). hnRNPK is a DNA-binding protein that can act as a transcription enhancer or repressor (56).…”

Section: Mass Spectroscopy; Acute (8 H) Groupmentioning

confidence: 99%

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

et al. 2020

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Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD + ). As a precursor for NAD + , Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD + levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e.g., lipopolysaccharide (LPS) or pokeweed mitogen (PWM)] in macrophages, microglia, dendritic cells, and other cells of the immune system. NAD + serves numerous functions including energy production, the poly ADP ribose polymerization (PARP) reaction involved in DNA repair, and the activity of various enzymes such as the NAD + -dependent deacetylases known as sirtuins. We used highly specific antibodies to protein-coupled Quin to delineate cells that accumulate Quin as a key aspect of the response to immune stimulation and infection. Here, we describe Quin staining in the brain, spleen, and liver after LPS administration to the brain or systemic PWM administration. Quin expression was strong in immune cells in the periphery after both treatments, whereas very limited Quin expression was observed in the brain even after direct LPS injection. Immunoreactive cells exhibited diverse morphology ranging from foam cells to cells with membrane extensions related to cell motility. We also examined protein expression changes in the spleen after kynurenine administration. Acute (8 h) and prolonged (48 h) kynurenine administration led to significant changes in protein expression in the spleen, including multiple changes involved with cytoskeletal rearrangements associated with cell motility. Kynurenine administration resulted in several expression level changes in proteins associated with heat shock protein 90 (HSP90), a chaperone for the aryl-hydrocarbon receptor (AHR), which is the primary kynurenine Moffett et al.Quinolinate as Kynurenine Marker and NAD + Source metabolite receptor. We propose that cells with high levels of Quin are those that are currently releasing kynurenine pathway metabolites as well as accumulating Quin for sustained NAD + synthesis from tryptophan. Further, we propose that the kynurenine pathway may be linked to the regulation of cell motility in immune and cancer cells.

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Section: Mass Spectroscopy; Acute (8 H) Groupmentioning

confidence: 99%

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

et al. 2020

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“…Cancer malignancy, the main cause of high cancer-related mortality, is controlled by strict and precise control of gene expression. Accumulating evidences indicates that RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) are key players in post-transcriptional gene regulation by affecting multiple steps of gene expression such as splicing, mRNA export, mRNA localization, mRNA stability, and translation (14). RBPs and ncRNAs are also known to modulate multiple cancer traits related to cancer progression, for instance, rapid proliferation and high metastatic potential.…”

Section: Discussionmentioning

confidence: 99%

hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2

Lee

Shin

et al. 2020

Preprint

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Background: Malignant characteristics of cancers, represented by rapid cell proliferation and high metastatic potential, are a major cause of high cancer-related mortality. As a multifunctional RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) is closely associated with cancer progression in various types of cancers. In this study, we sought to identify hnRNPK-regulated long intergenic non-coding RNAs (lincRNAs) that play a critical role in the regulation of cancer malignancy.Methods: Malignant phenotypes including metastatic and proliferative potential were examined using Transwell invasion assay, cell counting, and colony forming assay. To search for hnRNPK-regulated lincRNAs, RNA sequencing was performed. Using small RNA sequencing followed by antisense oligonucleotide pull-down, lincRNA-associated miRNAs were selected. The association between miRNA and target mRNA was determined by Argonaute 2-immunoprecipitation and luciferase reporter assay. Results: We found that hnRNPK controlled malignant phenotypes including invasiveness, proliferation, and clonogenicity. RNA sequencing and functional studies revealed that LINC00263, a novel target of hnRNPK, is involved in the oncogenic functions of hnRNPK. Knockdown of LINC00263 mitigated the malignant capabilities. Conversely, increased malignant phenotypes were observed in LINC00263-overexpressing cells. We also found that miR-147a negatively regulates LINC00263 via direct interaction, thus suppressing malignant capabilities. Moreover, knockdown of hnRNPK and LINC00263 upregulated miR-147a, indicating that LINC00263 serves as a ceRNA for miR-147a. By analyzing RNA sequencing data and miRNA target prediction, calpain 2 (CAPN2) was identified as a putative target of miR-147a. Ago2-IP and luciferase reporter assay revealed that miR-147a suppressed CAPN2 expression by directly binding to the 3'UTR of CAPN2 mRNA. Additionally, we found that the weakened malignant capabilities following knockdown of hnRNPK or LINC00263 were restored by miR-147a inhibition or CAPN2 overexpression.Conclusions: Our findings demonstrate that hnRNPK-regulated LINC00263 plays an important role in cancer malignancy by acting as a miR-147a decoy and thus upregulating CAPN2.

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“…The exact mechanism of how hnRNPK can retain RNAs in the nucleus is however still unknown [69]. HnRNPK fulfills a wide variety of cellular functions, for example by acting as a transcription factor, regulating translation, and serving as a hub for various signaling pathways [141]. Numerous studies have observed oncogenic effects as well as a prognostic relevance of hnRNPK in different types of cancer, like breast, colorectal, and gastric cancer, where its overall levels are increased and it is aberrantly localized in the cytoplasm [142][143][144].…”

Section: Heterogeneous Nuclear Ribonucleoprotein K (Hnrnpk)mentioning

confidence: 99%

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

Jonas

Calin

Pichler

2020

IJMS

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The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments. Compared to protein-coding genes, lncRNAs are poorly conserved between different species and their expression levels are rather low [7,8]. Initially, this led to the belief that they were nothing but transcriptional noise [6][7][8]. Soon, however, it was discovered that lncRNAs do exhibit considerable functionality, for example as regulators of transcription [6][7][8]. Mechanisms of transcriptional regulation by lncRNAs are multifarious and can occur either in cis or in trans, meaning either closer to or further away from the lncRNA's site of transcription, respectively [6,7]. A frequent mechanism of transcriptional regulation via lncRNAs is the recruitment, or prevention of such, of components of chromatin or histone-modifying complexes, like polycomb repressive complexes or histone deacetylase complexes [11][12][13]. LncRNAs can also direct transcription factors or cofactors to promoter regions of genes and facilitate the formation of chromatin loops between distant enhancers and promoters, as observed for some eRNAs [9,[14][15][16][17]. Another way that they can impact transcription is by interfering with the RNA polymerase II transcription machinery, thereby blocking transcriptional initiation or elongation [18]. LncRNAs are important regulators not only at the level of transcription but also at the post-transcriptional level [6,7]. They regulate pre-mRNA splicing by interacting with splicing factors or with the mRNA itself [19][20][21][22]. A well-studied example for this is metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNA that interacts with serine/arginine (SR) spl...

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The emerging roles of hnRNPK

Abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an DNA/RNA-binding protein and regulates a wide range of biological processes and disease pathogenesis. It contains 3

Cited by 102 publications

References 110 publications

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

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