scholarly journals The Identification of RNA-Binding Proteins Functionally Associated with Tumor Progression in Gastrointestinal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3165
Author(s):  
Hiroaki Konishi ◽  
Shin Kashima ◽  
Takuma Goto ◽  
Katsuyoshi Ando ◽  
Aki Sakatani ◽  
...  
Keyword(s):  
Cell Growth ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Functional Screening ◽  
Aberrant Expression ◽  
Sirna Library

Previous investigations have indicated that RNA-binding proteins (RBPs) are key molecules for the development of organs, differentiation, cell growth and apoptosis in cancer cells as well as normal cells. A bioinformatics analysis based on the mRNA expression and a somatic mutational database revealed the association between aberrant expression/mutations of RBPs and cancer progression. However, this method failed to detect functional alterations in RBPs without changes in the expression, thus leading to false negatives. To identify major tumor-associated RBPs, we constructed an siRNA library based on the database of RBPs and assessed the influence on the growth of colorectal, pancreatic and esophageal cancer cells. A comprehensive analysis of siRNA functional screening findings using 1198 siRNAs targeting 416 RBPs identified 41 RBPs in which 50% inhibition of cell growth was observed in cancer cells. Among these RBPs, 12 showed no change in the mRNA expression and no growth suppression in non-cancerous cells when downregulated by specific siRNAs. We herein report for the first time cancer-promotive RBPs identified by a novel functional assessment using an siRNA library of RBPs combined with expressional and mutational analyses.

scholarly journals Control of Cytokine mRNA Expression by RNA-binding Proteins and microRNAs

2012 ◽  
Vol 91 (7) ◽  
pp. 651-658 ◽  
Author(s):  
V. Palanisamy ◽  
A. Jakymiw ◽  
E.A. Van Tubergen ◽  
N.J. D’Silva ◽  
K.L. Kirkwood
Keyword(s):  
Cancer Progression ◽  
Mrna Stability ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Periodontal Diseases ◽  
Pharyngeal Cancer ◽  
Cytokine Mrna ◽  
Mediators Of Inflammation ◽  
The Stability

Cytokines are critical mediators of inflammation and host defenses. Regulation of cytokines can occur at various stages of gene expression, including transcription, mRNA export, and post- transcriptional and translational levels. Among these modes of regulation, post-transcriptional regulation has been shown to play a vital role in controlling the expression of cytokines by modulating mRNA stability. The stability of cytokine mRNAs, including TNFα, IL-6, and IL-8, has been reported to be altered by the presence of AU-rich elements (AREs) located in the 3′-untranslated regions (3′UTRs) of the mRNAs. Numerous RNA-binding proteins and microRNAs bind to these 3′UTRs to regulate the stability and/or translation of the mRNAs. Thus, this paper describes the cooperative function between RNA-binding proteins and miRNAs and how they regulate AU-rich elements containing cytokine mRNA stability/degradation and translation. These mRNA control mechanisms can potentially influence inflammation as it relates to oral biology, including periodontal diseases and oral pharyngeal cancer progression.

scholarly journals Phase transition of fibrillarin LC domain regulates localization and protein interaction of fibrillarin

2021 ◽  
Vol 478 (4) ◽  
pp. 799-810
Author(s):  
Eunji Kim ◽  
Ilmin Kwon
Keyword(s):  
Phase Transition ◽  
Binding Proteins ◽  
Rna Binding ◽  
Cultured Cells ◽  
Rna Binding Proteins ◽  
Underlying Mechanism ◽  
Low Complexity ◽  
Breast Cancer Patients ◽  
Aberrant Expression ◽  
Fibrillar Component

A key nucleolar protein, fibrillarin, has emerged as an important pharmacological target as its aberrant expression and localization are related to tumorigenesis, chemoresistance and poor survival in breast cancer patients. Fibrillarin contains a N-terminal low complexity sequence (LC) domain with a skewed amino acid distribution, which is known to undergo a phase transition to liquid-like droplets. However, the underlying mechanism of the phase transition of the fibrillarin LC domain and its physiological function are still elusive. In this study, we show that the localization of fibrillarin and its association with RNA binding proteins is regulated by this phase transition. Phenylalanine-to-serine substitutions of the phenylalanine:glycine repeats in the fibrillarin LC domain impede its phase transition into liquid-like droplets, as well as the hydrogel-like state composed of polymers, and also its incorporation into hydrogel or liquid-like droplets composed of wild-type LC domains. When expressed in cultured cells, fibrillarin containing the mutant LC domain fails to localize to the dense fibrillar component of nucleoli in the same way as intact fibrillarin. Moreover, the phase transition of the fibrillarin LC domain is required for the interaction of fibrillarin with other RNA binding proteins, such as FUS, TAF15, DDX5 and DHX9. Taken together, the results suggest that the phenylalanine residues in the LC domain are critical for the phase transition of fibrillarin, which in turn regulates the sub-nucleolar localization of fibrillarin and its interaction with RNA binding proteins, providing a useful framework for regulating the function of fibrillarin.

Double-stranded RNA-binding Proteins and the Control of Protein Synthesis and Cell Growth

2001 ◽  
Vol 66 (0) ◽  
pp. 485-498 ◽  
Author(s):  
L.M. PARKER ◽  
I. FIERRO-MONTI ◽  
T.W. REICHMAN ◽  
S. GUNNERY ◽  
M.B. MATHEWS
Keyword(s):  
Protein Synthesis ◽  
Cell Growth ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Double Stranded Rna

AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5732-5740 ◽  
Author(s):  
Maria Baou ◽  
John D. Norton ◽  
John J. Murphy
Keyword(s):  
Cell Growth ◽  
Regulatory Networks ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Growth And Survival ◽  
Hematopoietic Malignancies ◽  
Gene Regulatory

Abstract Posttranscriptional mechanisms are now widely acknowledged to play a central role in orchestrating gene-regulatory networks in hematopoietic cell growth, differentiation, and tumorigenesis. Although much attention has focused on microRNAs as regulators of mRNA stability/translation, recent data have highlighted the role of several diverse classes of AU-rich RNA-binding protein in the regulation of mRNA decay/stabilization. AU-rich elements are found in the 3′-untranslated region of many mRNAs that encode regulators of cell growth and survival, such as cytokines and onco/tumor-suppressor proteins. These are targeted by a burgeoning number of different RNA-binding proteins. Three distinct types of AU-rich RNA binding protein (ARE poly-U–binding degradation factor-1/AUF1, Hu antigen/HuR/HuA/ELAVL1, and the tristetraprolin/ZFP36 family of proteins) are essential for normal hematopoiesis. Together with 2 further AU-rich RNA-binding proteins, nucleolin and KHSRP/KSRP, the functions of these proteins are intimately associated with pathways that are dysregulated in various hematopoietic malignancies. Significantly, all of these AU-rich RNA-binding proteins function via an interconnected network that is integrated with microRNA functions. Studies of these diverse types of RNA binding protein are providing novel insight into gene-regulatory mechanisms in hematopoiesis in addition to offering new opportunities for developing mechanism-based targeted therapeutics in leukemia and lymphoma.

scholarly journals Identification of a Novel AU-Rich Element in the 3′ Untranslated Region of Epidermal Growth Factor Receptor mRNA That Is the Target for Regulated RNA-Binding Proteins

2001 ◽  
Vol 21 (6) ◽  
pp. 2070-2084 ◽  
Author(s):  
L. A. Balmer ◽  
D. J. Beveridge ◽  
J. A. Jazayeri ◽  
A. M. Thomson ◽  
C. E. Walker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Mrna Stability ◽  
Breast Cancer Cells ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Growth Factor Receptor ◽  
Human Breast ◽  
Shift Analysis

ABSTRACT The epidermal growth factor receptor (EGF-R) plays an important role in the growth and progression of estrogen receptor-negative human breast cancers. EGF binds with high affinity to the EGF-R and activates a variety of second messenger pathways that affect cellular proliferation. However, the underlying mechanisms involved in the regulation of EGF-R expression in breast cancer cells are yet to be described. Here we show that the EGF-induced upregulation of EGF-R mRNA in two human breast cancer cell lines that overexpress EGF-R (MDA-MB-468 and BT-20) is accompanied by stabilization (>2-fold) of EGF-R mRNA. Transient transfections using a luciferase reporter identified a novel EGF-regulated ∼260-nucleotide (nt)cis-acting element in the 3′ untranslated region (3′-UTR) of EGF-R mRNA. This cis element contains two distinct AU-rich sequences (∼75 nt), EGF-R1A with two AUUUA pentamers and EGF-R2A with two AUUUUUA extended pentamers. Each independently regulated the mRNA stability of the heterologous reporter. Analysis of mutants of the EGF-R2A AU-rich sequence demonstrated a role for the 3′ extended pentamer in regulating basal turnover. RNA gel shift analysis identified cytoplasmic proteins (∼55 to 80 kDa) from breast cancer cells that bound specifically to the EGF-R1A and EGF-R2A cis-acting elements and whose binding activity was rapidly downregulated by EGF and phorbol esters. RNA gel shift analysis of EGF-R2A mutants identified a role for the 3′ extended AU pentamer, but not the 5′ extended pentamer, in binding proteins. These EGF-R mRNA-binding proteins were present in multiple human breast and prostate cancer cell lines. In summary, these data demonstrate a central role for mRNA stabilization in the control of EGF-R gene expression in breast cancer cells. EGF-R mRNA contains a novel complex AU-rich 260-nt cis-acting destabilizing element in the 3′-UTR that is bound by specific and EGF-regulatedtrans-acting factors. Furthermore, the 3′ extended AU pentamer of EGF-R2A plays a central role in regulating EGF-R mRNA stability and the binding of specific RNA-binding proteins. These findings suggest that regulated RNA-protein interactions involving this novel cis-acting element will be a major determinant of EGF-R mRNA stability.

scholarly journals BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells

2017 ◽  
Vol 216 (12) ◽  
pp. 4091-4105 ◽  
Author(s):  
Ming-Xin An ◽  
Si Li ◽  
Han-Bing Yao ◽  
Chao Li ◽  
Jia-Mei Wang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Aerobic Glycolysis ◽  
Ductal Adenocarcinoma ◽  
Aberrant Expression ◽  
Hexokinase 2 ◽  
Pancreatic Cancer Cells

Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

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