Identification of Dynamic RNA-Binding Proteins Uncovers a Cpeb4-Controlled Regulatory Cascade During Pathological Cell Growth of Cardiomyocytes

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.

Download Full-text

Targeted deletion of genes for eukaryotic RNA-binding proteins, Rbp1 and Rbp2, in the cyanobacteriumSynechococcussp. strain PCC7942: Rbp1 is indispensable for cell growth at low temperatures

FEMS Microbiology Letters ◽

10.1111/j.1574-6968.1999.tb13656.x ◽

1999 ◽

Vol 176 (1) ◽

pp. 155-161 ◽

Cited By ~ 9

Author(s):

Chieko Sugita ◽

Michinori Mutsuda ◽

Masahiro Sugiura ◽

Mamoru Sugita

Keyword(s):

Cell Growth ◽

Low Temperatures ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Targeted Deletion

Download Full-text

The RNA-binding protein RBP10 controls a regulatory cascade that defines bloodstream-form trypanosome identity

10.1101/076273 ◽

2016 ◽

Author(s):

Elisha Mugo ◽

Christine Clayton

Keyword(s):

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Surface Protein ◽

Bloodstream Form ◽

Tsetse Flies ◽

Regulatory Cascade ◽

Gene Expression Control

AbstractGene expression control in the pathogen Trypanosoma brucei relies almost exclusively on post-transcriptional mechanisms, so RNA binding proteins must assume the burden that is usually borne by transcription factors. T. brucei multiply in the blood of mammals as bloodstream forms, and in the midgut of Tsetse flies as procyclic forms. We show here that a single RNA-binding protein, RBP10, defines the bloodstream-form trypanosome differentiation state. Depletion of RBP10 from bloodstream-form trypanosomes gives cells that can grow only as procyclic forms; conversely, expression of RBP10 in procyclic forms converts them to bloodstream forms. RBP10 binds to procyclic-specific mRNAs containing an UAUUUUUU motif, targeting them for translation repression and destruction. Products of RBP10 target mRNAs include not only the major procyclic surface protein and enzymes of energy metabolism, but also protein kinases and stage-specific RNA-binding proteins: consequently, alterations in RBP10 trigger a regulatory cascade.

Download Full-text

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

Cancers ◽

10.3390/cancers13133165 ◽

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.

Download Full-text

Integrated Analysis of RNA-Binding Proteins in Glioma

Cancers ◽

10.3390/cancers12040892 ◽

2020 ◽

Vol 12 (4) ◽

pp. 892 ◽

Cited By ~ 2

Author(s):

Zhixing Wang ◽

Wanjun Tang ◽

Jiangang Yuan ◽

Boqin Qiang ◽

Wei Han ◽

...

Keyword(s):

Gene Ontology ◽

Survival Analysis ◽

Cell Growth ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Global Analysis ◽

The Cancer Genome Atlas ◽

Integrated Analysis ◽

Genome Atlas

RNA-binding proteins (RBPs) play important roles in many cancer types. However, RBPs have not been thoroughly and systematically studied in gliomas. Global analysis of the functional impact of RBPs will provide a better understanding of gliomagenesis and new insights into glioma therapy. In this study, we integrated a list of the human RBPs from six sources—Gerstberger, SONAR, Gene Ontology project, Poly(A) binding protein, CARIC, and XRNAX—which covered 4127 proteins with RNA-binding activity. The RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) (n = 699) and Chinese Glioma Genome Atlas (CGGA) (n = 325 + 693). We examined the differentially expressed genes (DEGs) using the R package DESeq2, and constructed a weighted gene co-expression network analysis (WGCNA) of RBPs. Furthermore, survival analysis was also performed based on the univariate and multivariate Cox proportional hazards regression models. In the WGCNA analysis, we identified a key module involved in the overall survival (OS) of glioblastomas. Survival analysis revealed eight RBPs (PTRF, FNDC3B, SLC25A43, ZC3H12A, LRRFIP1, HSP90B1, HSPA5, and BNC2) are significantly associated with the survival of glioblastoma patients. Another 693 patients within the CGGA database were used to validate the findings. Additionally, 3564 RBPs were classified into canonical and non-canonical RBPs depending on the domains that they contain, and non-canonical RBPs account for the majority (72.95%). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that some non-canonical RBPs may have functions in glioma. Finally, we found that the knockdown of non-canonical RBPs, PTRF, or FNDC3B can alone significantly inhibit the proliferation of LN229 and U251 cells. Simultaneously, RNA Immunoprecipitation (RIP) analysis indicated that PTRF may regulate cell growth and death- related pathways to maintain tumor cell growth. In conclusion, our findings presented an integrated view to assess the potential death risks of glioblastoma at a molecular level, based on the expression of RBPs. More importantly, we identified non-canonical RNA-binding proteins PTRF and FNDC3B, showing them to be potential prognostic biomarkers for glioblastoma.

Download Full-text