scholarly journals HuRdling Senescence: HuR Breaks BRAF-Induced Senescence in Melanocytes and Supports Melanoma Growth

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1299 ◽  
Author(s):  
Janika K. Liebig ◽  
Silke Kuphal ◽  
Anja Katrin Bosserhoff
Keyword(s):  
Malignant Melanoma ◽  
Untranslated Region ◽  
Rna Binding ◽  
Malignant Tumors ◽  
Regulatory Pathway ◽  
Therapeutic Approaches ◽  
Genetic Changes ◽  
First Time

In addition to genetic changes, post-transcriptional events strongly contribute to the progression of malignant tumors. The RNA-binding protein HuR (ELAVL1) is able to bind and stabilize a large group of target mRNAs, which contain AU-rich elements (ARE) in their 3′-untranslated region. We found HuR to be upregulated in malignant melanoma in vitro and in vivo, significantly correlating with progression in vivo. Additionally, we could show that miR-194-5p can regulate HuR expression level. HuR knockdown in melanoma cells led to the suppression of proliferation and the induction of cellular senescence. Interestingly, HuR overexpression was sufficient to inhibit senescence in BRAFV600E-expressing melanocytes and to force their growth. Here, MITF (Microphthalmia-associated transcription factor), a key player in suppressing senescence and an ARE containing transcript, is positively regulated by HuR. Our results show for the first time that the overexpression of HuR is an important part of the regulatory pathway in the development of malignant melanoma and functions as a switch to overcome oncogene-induced senescence and to support melanoma formation. These newly defined alterations may provide possibilities for innovative therapeutic approaches.

scholarly journals lncRNA CASC19 Contributes to Radioresistance of Nasopharyngeal Carcinoma by Promoting Autophagy via AMPK-mTOR Pathway

2021 ◽  
Vol 22 (3) ◽  
pp. 1407
Author(s):  
Hongxia Liu ◽  
Wang Zheng ◽  
Qianping Chen ◽  
Yuchuan Zhou ◽  
Yan Pan ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cell Line ◽  
Malignant Tumors ◽  
Underlying Mechanism ◽  
Mtor Pathway ◽  
Rna Seq ◽  
Cellular Autophagy ◽  
First Time

Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors and is majorly treated by radiotherapy. However, radiation resistance remains a serious obstacle to the successful treatment of NPC. The aim of this study was to discover the underlying mechanism of radioresistance and to elucidate novel genes that may play important roles in the regulation of NPC radiosensitivity. By using RNA-seq analysis of NPC cell line CNE2 and its radioresistant cell line CNE2R, lncRNA CASC19 was screened out as a candidate radioresistance marker. Both in vitro and in vivo data demonstrated that a high expression level of CASC19 was positively correlated with the radioresistance of NPC, and the radiosensitivity of NPC cells was considerably enhanced by knockdown of CASC19. The incidence of autophagy was enhanced in CNE2R in comparison with CNE2 and another NPC cell line HONE1, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, CASC19 siRNA (siCASC19) suppressed cellular autophagy by inhibiting the AMPK/mTOR pathway and promoted apoptosis through the PARP1 pathway. Our results revealed for the first time that lncRNA CASC19 contributed to the radioresistance of NPC by regulating autophagy. In significance, CASC19 might be a potential molecular biomarker and a new therapeutic target in NPC.

scholarly journals Chondroitin polymerizing factor (CHPF) promotes development of malignant melanoma through regulation of CDK1

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Wei Sun ◽  
Fang Zhao ◽  
Yu Xu ◽  
Kai Huang ◽  
Xianling Guo ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Pathway Analysis ◽  
Normal Skin ◽  
Over Expression ◽  
Tumor Promotor ◽  
And Migration ◽  
First Time ◽  
The Relationship

Abstract Chondroitin polymerizing factor (CHPF) is an important member of glycosyltransferases involved in the biosynthesis of chondroitin sulfate (CS). However, the relationship between CHPF and malignant melanoma (MM) is still unknown. In this study, it was demonstrated that CHPF was up-regulated in MM tissues compared with the adjacent normal skin tissues and its high expression was correlated with more advanced T stage. Further investigations indicated that the over-expression/knockdown of CHPF could promote/inhibit proliferation, colony formation and migration of MM cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of CHPF could also suppress tumorigenicity of MM cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of CHPF and identified CDK1 as the potential target. Furthermore, our study revealed that knockdown of CDK1 could inhibit development of MM in vitro, and alleviate the CHPF over-expression induced promotion of MM. In conclusion, our study showed, as the first time, CHPF as a tumor promotor for MM, whose function was carried out probably through the regulation of CDK1.

RNA-binding protein CELF1 enhances cell migration, invasion, and chemoresistance by targeting ETS2 in colorectal cancer

2020 ◽  
Vol 134 (14) ◽  
pp. 1973-1990
Author(s):  
Huaiming Wang ◽  
Rongkang Huang ◽  
Wentai Guo ◽  
Xiusen Qin ◽  
Zifeng Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Malignant Tumors ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tumor Growth Model

Abstract Colorectal cancer (CRC) is often diagnosed at later stages after it has metastasized to other organs. The development of chemoresistance also contributes to a poor prognosis. Therefore, an increased understanding of the metastatic properties of CRC and chemoresistance could improve patient survival. CUGBP elav-like family member 1 (CELF1) is an RNA-binding protein, which is overexpressed in many human malignant tumors. However, the influence of CELF1 in CRC is unclear. V-ets erythroblastosis virus E26 oncogene homologue 2 (ETS2) is an evolutionarily conserved proto-oncogene known to be overexpressed in a variety of human cancers including CRC. In thespresent tudy, we investigated the association between CELF1 and ETS2 in CRC tumorigenesis and oxaliplatin (L-OHP) resistance. We found a positive correlation between the elevated expression of CELF1 and ETS2 in human CRC tissues. Overexpression of CELF1 increased CRC cell proliferation, migration, and invasion in vitro and in a xenograft tumor growth model in vivo, and induced resistance to L-OHP. In contrast, CELF1 knockdown improved the response of CRC cells to L-OHP. Overexpression of ETS2 increased the malignant behavior of CRC cells (growth, migration, and invasion) and L-OHP resistance in vitro. Moreover, L-OHP resistance induced by CELF1 overexpression was reversed by ETS2 knockdown. The results of luciferase reporter and ribonucleoprotein immunoprecipitation assays indicated that CELF1 up-regulates ETS2 by binding to its 3′-UTR. Taken together, our findings have identified that CELF1 regulates ETS2 in a mechanism that results in CRC tumorigenesis and L-OHP resistance, and CELF1 may be a promising target for overcoming chemoresistance in CRC.

scholarly journals Structural and Functional Analysis of an mRNP Complex That Mediates the High Stability of Human β-Globin mRNA

2001 ◽  
Vol 21 (17) ◽  
pp. 5879-5888 ◽  
Author(s):  
Jia Yu ◽  
J. Eric Russell
Keyword(s):  
Mrna Stability ◽  
Rna Binding ◽  
Assembly Sequence ◽  
Regulatory Pathway ◽  
Globin Mrna ◽  
Mrnp Complex ◽  
The Stability ◽  
High Level

ABSTRACT Human globins are encoded by mRNAs exhibiting high stabilities in transcriptionally silenced erythrocyte progenitors. Unlike α-globin mRNA, whose stability is enhanced by assembly of a specific messenger RNP (mRNP) α complex on its 3′ untranslated region (UTR), neither the structure(s) nor the mechanism(s) that effects the high-level stability of human β-globin mRNA has been identified. The present work describes an mRNP complex assembling on the 3′ UTR of the β-globin mRNA that exhibits many of the properties of the stability-enhancing α complex. The β-globin mRNP complex is shown to contain one or more factors homologous to αCP, a 39-kDa RNA-binding protein that is integral to α-complex assembly. Sequence analysis implicates a specific 14-nucleotide pyrimidine-rich track within its 3′ UTR as the site of β-globin mRNP assembly. The importance of this track to mRNA stability is subsequently verified in vivo using mice expressing human β-globin transgenes that contain informative mutations in this region. In combination, the in vitro and in vivo analyses indicate that the high stabilities of the α- and β-globin mRNAs are maintained through related mRNP complexes that may share a common regulatory pathway.

scholarly journals MSY2 and MSY4 Bind a Conserved Sequence in the 3′ Untranslated Region of Protamine 1 mRNA In Vitro and In Vivo

2001 ◽  
Vol 21 (20) ◽  
pp. 7010-7019 ◽  
Author(s):  
Flaviano Giorgini ◽  
Holly G. Davies ◽  
Robert E. Braun
Keyword(s):  
Untranslated Region ◽  
Rna Binding ◽  
Mutational Analysis ◽  
Binding Activity ◽  
Mobility Shift ◽  
Conserved Sequence ◽  
Mobility Shift Assay ◽  
Protamine 1

ABSTRACT Y-box proteins are major constituents of ribonucleoprotein particles (RNPs) which contain translationally silent mRNAs in gametic cells. We have recently shown that a sequence-specific RNA binding activity present in spermatogenic cells contains the two Y-box proteins MSY2 and MSY4. We show here that MSY2 and MSY4 bind a sequence, 5′-UCCAUCA-3′, present in the 3′ untranslated region of the translationally repressed protamine 1 (Prm1) mRNA. Using pre- and post-RNase T1-digested substrate RNAs, it was determined that MSY2 and MSY4 can bind an RNA of eight nucleotides containing the MSY2 and MSY4 binding site. Single nucleotide mutations in the sequence eliminated the binding of MSY2 and MSY4 in an electrophoretic mobility shift assay, and the resulting mutants failed to compete for binding in a competition assay. A consensus site of UACCACAUCCACU(subscripts indicate nucleotides which do not disrupt YRS binding by MSY2 and MSY4), denoted the Y-box recognition site (YRS), was defined from this mutational analysis. These mutations in the YRS were further characterized in vivo using a novel application of the yeast three-hybrid system. Experiments with transgenic mice show that disruption of the YRS in vivo relieves Prm1-like repression of a reporter gene. The conservation of the RNA binding motifs among Y-box protein family members raises the possibility that other Y-box proteins may have previously unrecognized sequence-specific RNA binding activities.

scholarly journals A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo

2006 ◽  
Vol 26 (6) ◽  
pp. 2419-2429 ◽  
Author(s):  
Yong Jiang ◽  
Xiang-Sheng Xu ◽  
J. Eric Russell
Keyword(s):  
Mrna Stability ◽  
Untranslated Region ◽  
Rna Binding ◽  
Critical Role ◽  
Specific Interaction ◽  
Globin Mrna ◽  
Intact Cells ◽  
Normal Expression

ABSTRACT The normal expression of human β globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with α-globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing β-globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the β-globin 3′ untranslated region (3′UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by αCP/hnRNP-E, a factor that plays a critical role in stabilizing human α-globin mRNA. Mutations within the new determinant destabilize β-globin mRNA in intact cells while also ablating its 3′UTR-specific interaction with the polyfunctional RNA-binding factor nucleolin. We speculate that 3′UTR-bound nucleolin enhances mRNA stability by optimizing αCP access to its functional binding site. This model is favored by in vitro evidence that αCP binding is enhanced both by cis-acting stem-destabilizing mutations and by the trans-acting effects of supplemental nucleolin. These studies suggest a mechanism for β-globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human α-globin mRNA.

scholarly journals RNA binding of Hfq monomers promotes RelA-mediated hexamerization in a limiting Hfq environment

2020 ◽  
Author(s):  
Pallabi Basu ◽  
Maya Elgrably-Weiss ◽  
Fouad Hassouna ◽  
Manoj Kumar ◽  
Reuven Wiener ◽  
...  
Keyword(s):  
Rna Binding ◽  
Response Regulator ◽  
Stringent Response ◽  
Rna Biogenesis ◽  
Unstable Complex ◽  
Post Transcriptional Regulation ◽  
First Time ◽  
Initial Binding

AbstractThe RNA chaperone Hfq acting as a hexamer, is a known mediator of post-transcriptional regulation expediting basepairing between small RNAs (sRNAs) and their target mRNAs. However, the intricate details associated with Hfq-RNA biogenesis are still unclear. Previously, we reported that the stringent response regulator, RelA is a functional partner of Hfq that facilitates Hfq-mediated sRNA-mRNA regulation in vivo and induces Hfq hexamerization in vitro. Here, for the first time we show that RelA-mediated Hfq hexamerization requires an initial binding of RNA, preferably sRNA to Hfq monomers. By interacting with a Shine-Dalgarno-like sequence (GGAG) in the sRNA, RelA stabilizes the initially unstable complex of RNA bound-Hfq monomer, enabling the attachment of more Hfq subunits to form a functional hexamer. Overall, our study showing that RNA binding to Hfq monomers is at the heart of RelA-mediated Hfq hexamerization, challenges the previous concept that only Hfq hexamers can bind RNA.

scholarly journals Role for Upf2p Phosphorylation in Saccharomyces cerevisiae Nonsense-Mediated mRNA Decay

2006 ◽  
Vol 26 (9) ◽  
pp. 3390-3400 ◽  
Author(s):  
Weirong Wang ◽  
Iván J. Cajigas ◽  
Stuart W. Peltz ◽  
Miles F. Wilkinson ◽  
Carlos I. González
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mrna Decay ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Nonsense Mediated Mrna Decay ◽  
Higher Eukaryotes ◽  
Nonsense Codons ◽  
First Time

ABSTRACT Premature termination (nonsense) codons trigger rapid mRNA decay by the nonsense-mediated mRNA decay (NMD) pathway. Two conserved proteins essential for NMD, UPF1 and UPF2, are phosphorylated in higher eukaryotes. The phosphorylation and dephosphorylation of UPF1 appear to be crucial for NMD, as blockade of either event in Caenorhabditis elegans and mammals largely prevents NMD. The universality of this phosphorylation/dephosphorylation cycle pathway has been questioned, however, because the well-studied Saccharomyces cerevisiae NMD pathway has not been shown to be regulated by phosphorylation. Here, we used in vitro and in vivo biochemical techniques to show that both S. cerevisiae Upf1p and Upf2p are phosphoproteins. We provide evidence that the phosphorylation of the N-terminal region of Upf2p is crucial for its interaction with Hrp1p, an RNA-binding protein that we previously showed is essential for NMD. We identify specific amino acids in Upf2p's N-terminal domain, including phosphorylated serines, which dictate both its interaction with Hrp1p and its ability to elicit NMD. Our results indicate that phosphorylation of UPF1 and UPF2 is a conserved event in eukaryotes and for the first time provide evidence that Upf2p phosphorylation is crucial for NMD.

scholarly journals The 3′ Untranslated Region Complex Involved in Stabilization of Human α-globin mRNA Assembles in the Nucleus and Serves an Independent Role as a Splice Enhancer

2007 ◽  
Vol 27 (9) ◽  
pp. 3290-3302 ◽  
Author(s):  
Xinjun Ji ◽  
Jian Kong ◽  
Russ P. Carstens ◽  
Stephen A. Liebhaber
Keyword(s):  
Untranslated Region ◽  
Rna Binding ◽  
Protein Complexes ◽  
Binding Protein ◽  
Splice Enhancer ◽  
Globin Mrna ◽  
Nuclear Assembly ◽  
General Importance

ABSTRACT Posttranscriptional controls, mediated primarily by RNA-protein complexes, have the potential to alter multiple steps in RNA processing and function. Human α-globin mRNA is bound at a C-rich motif in the 3′ untranslated region (3′UTR) by the KH domain protein α-globin poly(C)-binding protein (αCP). This “α-complex” is essential to cytoplasmic stability of α-globin mRNA in erythroid cells. Here we report that the 3′UTR α-complex also serves an independent nuclear role as a splice enhancer. Consistent with this role, we find that αCP binds α-globin transcripts prior to splicing. Surprisingly, this binding occurs at C-rich sites within intron I as well as at the 3′UTR C-rich determinant. The intronic and 3′UTR αCP complexes appear to have distinct effects on splicing. While intron I complexes repress intron I excision, the 3′UTR complex enhances splicing of the full-length transcript both in vivo and in vitro. In addition to its importance to splicing, nuclear assembly of the 3′UTR αCP complex may serve to “prepackage” α-globin mRNA with its stabilizing complex prior to cytoplasmic export. Linking nuclear and cytoplasmic controls by the action of a particular RNA-binding protein, as reported here, may represent a modality of general importance in eukaryotic gene regulation.

scholarly journals PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zhiqiang Han ◽  
Dongming Liu ◽  
Lu Chen ◽  
Yuchao He ◽  
Xiangdong Tian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Malignant Tumors ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Hcc Cells

AbstractSome studies have reported that activated ribosomes are positively associated with malignant tumors, especially in hepatocellular carcinoma (HCC). The RNA-binding protein PNO1 is a critical ribosome rarely reported in human tumors. This study aimed to explore the molecular mechanisms of PNO1 in HCC. Using 150 formalin-fixed and paraffin-embedded samples and 8 fresh samples, we found high PNO1 expression in HCC tumor tissues through Western blotting and RT-PCR. Moreover, the higher PNO1 expression was associated with poor HCC prognosis patients. In vitro and in vivo experiments indicated that PNO1 overexpression promoted the proliferation and depressed the apoptosis of HCC cells. High PNO1 expression also increased the autophagy of HCC cells. The molecular mechanisms underlying PNO1 were examined by RNA-seq analysis and a series of functional experiments. Results showed that PNO1 promoted HCC progression through the MAPK signaling pathway. Therefore, PNO1 was overexpressed in HCC, promoted autophagy, and inhibited the apoptosis of HCC cells through the MAPK signaling pathway.

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