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Layla A Al-Kharashi, Falah H Al-Mohanna, Asma Tulbah, Abdelilah Aboussekhra
The activation of breast stromal fibroblasts is a crucial step toward tumor growth and spread. Therefore, it is extremely important to understand the molecular basis of this activation and determine the molecules and the mechanisms responsible for its sustainability. In the present report we have shown that the DNA methyl-transferase protein DNMT1 is critical for the activation of breast stromal fibroblasts as well as the persistence of their active status. Indeed, we have first revealed DNMT1 up-regulation in most cancer-associated fibroblasts relative to their corresponding adjacent normal fibroblasts...
January 5, 2018: Oncotarget
Tala Bakheet, Edward Hitti, Maher Al-Saif, Walid N Moghrabi, Khalid S A Khabar
Adenylate-uridylate (AU)-rich elements (AREs) are sequence instability elements that are known to be located in the 3' untranslated regions (UTR) in thousands of human transcripts. AREs regulate the expression of many genes at the post-transcriptional level, and they are essential for many normal cellular functions. We conducted a transcriptome-wide screen for AREs and found that they are most abundant in introns, with up to 25% of introns containing AREs corresponding to 58% of human genes. Clustering studies of ARE size, complexity, and distribution revealed that, in introns, longer AREs with two or more overlapping repeats are more abundant than in the 3'UTR, and only introns can contain very long AREs with 6-14 overlapping AUUUA pentamers...
February 1, 2018: Biochimica et Biophysica Acta
Yi-Fan Zhou, Ya-Nan Li, Hui-Juan Jin, Jie-Hong Wu, Quan-Wei He, Xu-Xia Wang, Hao Lei, Bo Hu
The inflammatory process in stroke is the major contributor to blood-brain barrier (BBB) breakdown. Previous studies indicated that semaphorin 4D (Sema4D), an axon guidance molecule, initiated inflammatory microglial activation and disrupted endothelial function in the CNS. However, whether Sema4D disrupts BBB integrity after stroke remains unclear. To study the effect of Sema4D on BBB disruption in stroke, rats were subjected to transient middle cerebral artery occlusion and targeted injection of lentivirus-mediated clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene disruption of PlexinB1...
December 14, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jian He, Ya-Feng Jiang, Liu Liang, Du-Jin Wang, Wen-Xin Wei, Pan-Pan Ji, Yao-Chan Huang, Hui Song, Xiao-Ling Lu, Yong-Xiang Zhao
BACKGROUND: Inhibition of aging of vascular endothelial cells (VECs) may delay aging and prolong life. The goal of this study was to prepare anti-CD31 monoclonal antibody conjugated PEG-modified liposomes containing the AU-rich region connecting factor 1 (AUF1) gene (CD31-PILs-AUF1) and to explore the effects of targeting CD31-PILs-AUF1 to aging VECs. METHODS: The mean particle sizes of various PEGylated immunoliposomes (PILs) were measured using a Zetasizer Nano ZS...
August 2017: Journal of Geriatric Cardiology: JGC
Jing Yan, Feng Du, Sheng-Dong Li, Ye Yuan, Jing-Yi Jiang, Si Li, Xin-Yu Li, Zhen-Xian Du
Posttranscriptional regulation process plays important roles in renal disease pathogenesis. AU-rich element RNA-binding protein (AUF1) interacts with and destabilizes mRNAs containing AU-rich elements (AREs) in their 3'UTR. The current study demonstrated that AUF1 was increased in unilateral ureteral obstruction (UUO) animal models. While proliferation and migration of HK2 cells was unaltered by AUF1 downregulation under normal condition, proliferative inhibition and migratory promotion mediated by TGF-β was significantly compromised...
October 3, 2017: Biochimica et Biophysica Acta
Zhen-Dong Xiao, Leng Han, Hyemin Lee, Li Zhuang, Yilei Zhang, Joelle Baddour, Deepak Nagrath, Christopher G Wood, Jian Gu, Xifeng Wu, Han Liang, Boyi Gan
The roles of long non-coding RNAs in cancer metabolism remain largely unexplored. Here we identify FILNC1 (FoxO-induced long non-coding RNA 1) as an energy stress-induced long non-coding RNA by FoxO transcription factors. FILNC1 deficiency in renal cancer cells alleviates energy stress-induced apoptosis and markedly promotes renal tumor development. We show that FILNC1 deficiency leads to enhanced glucose uptake and lactate production through upregulation of c-Myc. Upon energy stress, FILNC1 interacts with AUF1, a c-Myc mRNA-binding protein, and sequesters AUF1 from binding c-Myc mRNA, leading to downregulation of c-Myc protein...
October 4, 2017: Nature Communications
Silvia Mrvová, Klára Frydrýšková, Martin Pospíšek, Václav Vopálenský, Tomáš Mašek
Alternative polyadenylation is an important and pervasive mechanism that generates heterogeneous 3'-termini of mRNA and is considered an important regulator of gene expression. We performed bioinformatics analyses of ESTs and the 3'-UTRs of the main transcript splice variants of the translational initiation factor eIF4E1 and its family members, eIF4E2 and eIF4E3. This systematic analysis led to the prediction of new polyadenylation signals. All identified polyadenylation sites were subsequently verified by 3'RACE of transcripts isolated from human lymphoblastic cell lines...
September 23, 2017: Molecular Genetics and Genomics: MGG
Osamu Takeuchi
The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co-stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA-binding proteins (RBPs), including Regnase-1, Roquin, Tristetraprolin (TTP), and AU-rich elements/poly(U)-binding/degradation factor 1 (AUF1)...
September 20, 2017: Wiley Interdisciplinary Reviews. RNA
Kyung-Won Min, Myung Hyun Jo, Soochul Shin, Sylvia Davila, Richard W Zealy, Soo Im Kang, Lawson T Lloyd, Sungchul Hohng, Je-Hyun Yoon
Eukaryotic mRNA decay is tightly modulated by RNA-binding proteins (RBPs) and microRNAs (miRNAs). RBP AU-binding factor 1 (AUF1) has four isoforms resulting from alternative splicing and is critical for miRNA-mediated gene silencing with a distinct preference of target miRNAs. Previously, we have shown that AUF1 facilitates miRNA loading to Argonaute 2 (AGO2), the catalytic component of the RNA-induced silencing complex. Here, we further demonstrate that depletion of AUF1 abolishes the global interaction of miRNAs and AGO2...
June 2, 2017: Nucleic Acids Research
Apostolia Fragkouli, Pelagia Koukouraki, Ioannis S Vlachos, Maria D Paraskevopoulou, Artemis G Hatzigeorgiou, Epaminondas Doxakis
Aβ peptide that accumulates in Alzheimer's disease brain, derives from proteolytic processing of the amyloid precursor protein (APP) that exists in three main isoforms derived by alternative splicing. The isoform APP695, lacking exons 7 and 8, is predominately expressed in neurons and abnormal neuronal splicing of APP has been observed in the brain of patients with Alzheimer's disease. Herein, we demonstrate that expression of the neuronal members of the ELAVL protein family (nELAVLs) correlate with APP695 levels in vitro and in vivo...
March 14, 2017: Scientific Reports
Smita Shukla, Genie Elson, Perry J Blackshear, Carol S Lutz, S Joseph Leibovich
We have shown previously that bacterial lipopolysaccharide (LPS)-mediated suppression of phospholipase-Cβ-2 (PLCβ-2) expression is involved in M1 (inflammatory) to M2-like (wound healing) phenotypic switching of macrophages triggered by adenosine. This suppression is mediated post-transcriptionally by destabilization of PLCβ-2 mRNA (messenger ribonucleic acid). To investigate the mechanism of this LPS-mediated destabilization, we examined the roles of RNA-binding agents including microRNAs and RNA-binding proteins that are involved in regulating stability of mRNAs encoding growth factors, inflammatory mediators, and proto-oncogenes...
April 2017: Inflammation
Cheol Kyu Hwang, Yadav Wagley, Ping-Yee Law, Li-Na Wei, Horace H Loh
Gene regulation at the post-transcriptional level is frequently based on cis- and trans-acting factors on target mRNAs. We found a C-rich element (CRE) in mu-opioid receptor (MOR) 3'-untranslated region (UTR) to which poly (rC) binding protein 1 (PCBP1) binds, resulting in MOR mRNA stabilization. RNA immunoprecipitation and RNA EMSA revealed the formation of PCBP1-RNA complexes at the element. Knockdown of PCBP1 decreased MOR mRNA half-life and protein expression. Stimulation by forskolin increased cytoplasmic localization of PCBP1 and PCBP1/MOR 3'-UTR interactions via increased serine phosphorylation that was blocked by protein kinase A (PKA) or (phosphatidyl inositol-3) PI3-kinase inhibitors...
January 20, 2017: Gene
Yi Gao, Wenjie Wang, Jinming Cao, Fangjun Wang, Yangyang Geng, Jianping Cao, Xiaohui Xu, Jundong Zhou, Pengfei Liu, Shuyu Zhang
Esophageal squamous cell carcinoma (ESCC) has one of the highest mortality rates worldwide. AU-rich element RNA-binding factor 1 (AUF1) is an established RNA-binding protein. AUF1 influences the process of development, apoptosis and tumorigenesis via interacting with adenylate-uridylate rich elements (AREs) bearing mRNAs. However, the clinical relevance of AUF1 and its biological function in ESCC progression have not been reported. In the present study, we first investigated the expression of AUF1 in the ESCC tissue samles and normal samples...
November 2016: International Journal of Oncology
Shuhong Sun, Xiaotian Zhang, Lin Lyu, Xixi Li, Siliang Yao, Junjie Zhang
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a lysophospholipid mediator that regulates cellular activities through its specific G protein-coupled receptors. The ATX-LPA axis plays an important role in various physiological and pathological processes, especially in inflammation and cancer development. Although the transcriptional regulation of ATX has been widely studied, the post-transcriptional regulation of ATX is largely unknown. In this study, we identified conserved adenylate-uridylate (AU)-rich elements in the ATX mRNA 3'-untranslated region (3'UTR)...
December 9, 2016: Journal of Biological Chemistry
Si Li, Hai-Yan Zhang, Zhen-Xian Du, Chao Li, Ming-Xin An, Zhi-Hong Zong, Bao-Qin Liu, Hua-Qin Wang
Beclin 1 has emerged as a haploinsufficient tumor suppression gene in a variety of human carcinomas. In order to clarify the role of Beclin 1 in thyroid cancer, Beclin 1 was knockdown in thyroid cancer cell lines. The current study demonstrated that knockdown of Beclin 1 resulted in morphological and molecular changes of thyroid cancer cells consistent with epithelial-mesenchymal transition (EMT), a morphogenetic procedure during which cells lose their epithelial characteristics and acquire mesenchymal properties concomitantly with gene expression reprogramming...
October 25, 2016: Oncotarget
Elizabeth J F White, Aerielle E Matsangos, Gerald M Wilson
AUF1 is a family of four RNA-binding proteins (RBPs) generated by alternative pre-messenger RNA (pre-mRNA) splicing, with canonical roles in controlling the stability and/or translation of mRNA targets based on recognition of AU-rich sequences within mRNA 3' untranslated regions. However, recent studies identifying AUF1 target sites across the transcriptome have revealed that these canonical functions are but a subset of its roles in posttranscriptional regulation of gene expression. In this review, we describe recent developments in our understanding of the RNA-binding properties of AUF1 together with their biochemical implications and roles in directing mRNA decay and translation...
March 2017: Wiley Interdisciplinary Reviews. RNA
Huda H Al-Khalaf, Abdelilah Aboussekhra
Senescence and epithelial-to-mesenchymal transition (EMT) processes are under the control of common tumor suppressor proteins, EMT transcription factors, and microRNAs. However, the molecular mechanisms that coordinate the functional link between senescence and EMT are still elusive. We have shown here that p16(INK4A) -related induction of senescence is mediated through miR-141 and miR-146b-5p. These two microRNAs are up-regulated in aging human fibroblast and epithelial cells. Furthermore, miR-141 and miR146b-5p trigger cell cycle arrest at G1 phase and induce senescence in primary human fibroblasts and breast cancer cells in the presence and absence of p16(INK4A) ...
March 2017: Molecular Carcinogenesis
Jiahui Chen, Lihui Liu, Guifeng Wei, Wei Wu, Huaxia Luo, Jiao Yuan, Jianjun Luo, Runsheng Chen
The identification and characterization of long non-coding RNAs (lncRNAs) in diverse biological processes has recently developed rapidly. The large amounts of non-coding RNAs scale consistent with developmental complexity in eukaryotes, indicating that most of these transcripts may have functions in the regulation of biological processes and disorder in the organisms. In particular, Understanding of the overall biological significance of lncRNAs in cancers still remains limited. Here, we found a nuclear-retained lncRNA, termed Lnc_ASNR (apoptosis suppressing-noncoding RNA), which serves as a repressor of apoptosis...
August 31, 2016: Scientific Reports
Zdenka Navratilova, Eva Novosadova, Michael Hagemann-Jensen, Susanna Kullberg, Vitezslav Kolek, Johan Grunewald, Martin Petrek
BACKGROUND: Sarcoidosis is characterised by up-regulation of cytokines and chemokine ligands/receptors and proteolytic enzymes. This pro-inflammatory profile is regulated post-transcriptionally by RNA-binding proteins (RBPs). We investigated in vivo expression of six RBPs (AUF1, HuR, NCL, TIA, TIAR, PCBP2) and two inhibitors of proteolytic enzymes (RECK, PTEN) in pulmonary sarcoidosis and compared it to the expression in four control groups of healthy individuals and patients with other respiratory diseases: chronic obstructive pulmonary disease (COPD), asthma and idiopathic interstitial pneumonias (IIPs)...
2016: PloS One
Susann Friedrich, Tobias Schmidt, Angelika Schierhorn, Hauke Lilie, Grit Szczepankiewicz, Sandra Bergs, Uwe G Liebert, Ralph P Golbik, Sven-Erik Behrens
A prerequisite for the intracellular replication process of the Flavivirus West Nile virus (WNV) is the cyclization of the viral RNA genome, which enables the viral replicase to initiate RNA synthesis. Our earlier studies indicated that the p45 isoform of the cellular AU-rich element binding protein 1 (AUF1) has an RNA chaperone activity, which supports RNA cyclization and viral RNA synthesis by destabilizing a stem structure at the WNV RNA's 3'-end. Here we show that in mammalian cells, AUF1 p45 is consistently modified by arginine methylation of its C terminus...
October 2016: RNA
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