scholarly journals The Nuclear Splicing Factor RNA Binding Motif 5 Promotes Caspase Activation in Human Neuronal Cells, and Increases after Traumatic Brain Injury in Mice

2015 ◽  
Vol 35 (4) ◽  
pp. 655-666 ◽  
Author(s):  
Travis C Jackson ◽  
Lina Du ◽  
Keri Janesko-Feldman ◽  
Vincent A Vagni ◽  
Cameron Dezfulian ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Rna Binding ◽  
Neuronal Cells ◽  
Splicing Factor ◽  
Binding Motif ◽  
Caspase Activation ◽  
Caspase 2 ◽  
Human Neuronal Cells ◽  
Rna Binding Motif 5

Splicing factors (SFs) coordinate nuclear intron/exon splicing of RNA. Splicing factor disturbances can cause cell death. RNA binding motif 5 (RBM5) and 10 (RBM10) promote apoptosis in cancer cells by activating detrimental alternative splicing of key death/survival genes. The role(s) of RBM5/10 in neurons has not been established. Here, we report that RBM5 knockdown in human neuronal cells decreases caspase activation by staurosporine. In contrast, RBM10 knockdown augments caspase activation. To determine whether brain injury alters RBM signaling, we measured RBM5/10 protein in mouse cortical/hippocampus homogenates after controlled cortical impact (CCI) traumatic brain injury (TBI) plus hemorrhagic shock (CCI+HS). The RBM5/10 staining was higher 48  to 72 hours after injury and appeared to be increased in neuronal nuclei of the hippocampus. We also measured levels of other nuclear SFs known to be essential for cellular viability and report that splicing factor 1 (SF1) but not splicing factor 3A (SF3A) decreased 4  to 72 hours after injury. Finally, we confirm that RBM5/10 regulate protein expression of several target genes including caspase-2, cellular FLICE-like inhibitory protein (c-FLIP), LETM1 Domain-Containing Protein 1 (LETMD1), and amyloid precursor-like protein 2 (APLP2) in neuronal cells. Knockdown of RBM5 appeared to increase expression of c-FLIP(s), LETMD1, and APLP2 but decrease caspase-2.

scholarly journals The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 883
Author(s):  
Anna Gaertner ◽  
Julia Bloebaum ◽  
Andreas Brodehl ◽  
Baerbel Klauke ◽  
Katharina Sielemann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Early Onset ◽  
Target Genes ◽  
Frameshift Mutation ◽  
Rna Binding ◽  
Splicing Factor ◽  
Binding Motif ◽  
Rich Domain ◽  
Generation Sequencing

A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20.

scholarly journals Impulsive Pressurization of Neuronal Cells for Traumatic Brain Injury Study

10.3791/2723 ◽  
2011 ◽  
Author(s):  
Matthew Nienaber ◽  
Jeong Soon Lee ◽  
Ruqiang Feng ◽  
Jung Yul Lim
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Cells

scholarly journals Decreased RNA-binding motif 5 expression is associated with tumor progression in gastric cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769454 ◽  
Author(s):  
Takahiko Kobayashi ◽  
Junich Ishida ◽  
Yuichi Shimizu ◽  
Hiroshi Kawakami ◽  
Goki Suda ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Protein Expression ◽  
Cancer Cells ◽  
Rna Binding ◽  
Suppressor Gene ◽  
Binding Motif ◽  
Gastric Cancer Cells ◽  
Rna Binding Motif 5

RNA-binding motif 5 is a putative tumor suppressor gene that modulates cell cycle arrest and apoptosis. We recently demonstrated that RNA-binding motif 5 inhibits cell growth through the p53 pathway. This study evaluated the clinical significance of RNA-binding motif 5 expression in gastric cancer and the effects of altered RNA-binding motif 5 expression on cancer biology in gastric cancer cells. RNA-binding motif 5 protein expression was evaluated by immunohistochemistry using the surgical specimens of 106 patients with gastric cancer. We analyzed the relationships of RNA-binding motif 5 expression with clinicopathological parameters and patient prognosis. We further explored the effects of RNA-binding motif 5 downregulation with short hairpin RNA on cell growth and p53 signaling in MKN45 gastric cancer cells. Immunohistochemistry revealed that RNA-binding motif 5 expression was decreased in 29 of 106 (27.4%) gastric cancer specimens. Decreased RNA-binding motif 5 expression was correlated with histological differentiation, depth of tumor infiltration, nodal metastasis, tumor–node–metastasis stage, and prognosis. RNA-binding motif 5 silencing enhanced gastric cancer cell proliferation and decreased p53 transcriptional activity in reporter gene assays. Conversely, restoration of RNA-binding motif 5 expression suppressed cell growth and recovered p53 transactivation in RNA-binding motif 5–silenced cells. Furthermore, RNA-binding motif 5 silencing reduced the messenger RNA and protein expression of the p53 target gene p21. Our results suggest that RNA-binding motif 5 downregulation is involved in gastric cancer progression and that RNA-binding motif 5 behaves as a tumor suppressor gene in gastric cancer.

Cytochrome c release and caspase activation after traumatic brain injury

2002 ◽  
Vol 949 (1-2) ◽  
pp. 88-96 ◽  
Author(s):  
Patrick G Sullivan ◽  
Jeffrey N Keller ◽  
Wendy L Bussen ◽  
Stephen W Scheff
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cytochrome C ◽  
Caspase Activation ◽  
Cytochrome C Release

scholarly journals Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

2021 ◽  
Vol 11 (2) ◽  
pp. 130
Author(s):  
Paloma Jordà ◽  
Rocío Toro ◽  
Carles Diez ◽  
Joel Salazar-Mendiguchía ◽  
Anna Fernandez-Falgueras ◽  
...  
Keyword(s):  
Rna Binding ◽  
Preventive Measures ◽  
Rare Variants ◽  
Early Recognition ◽  
Splicing Factor ◽  
Binding Motif ◽  
Familial Dilated Cardiomyopathy ◽  
Specific Alternative ◽  
Personalized Approach ◽  
Malignant Arrhythmias

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.

scholarly journals Systematic characterization of branch point binding protein, splicing factor 1, gene family in plant development and stress responses

2019 ◽  
Author(s):  
Kai-Lu Zhang ◽  
Zhen Feng ◽  
Jing-Fang Yang ◽  
Tian Yuan ◽  
Di Zhang ◽  
...  
Keyword(s):  
Gene Family ◽  
Plant Species ◽  
Stress Responses ◽  
Messenger Rna ◽  
Rna Binding ◽  
Binding Protein ◽  
Splicing Factor ◽  
Binding Motif ◽  
Splicing Factor 1

Abstract Background: Among eukaryotic organisms, the splicing of nuclear precursor messenger RNA (pre-mRNA) is a process of introns excision and sequentially joining of exons, leading multi-exonic genes to generate multiple splicing isoforms at transcription level. This process is carried out by a super-protein complex defined as spliceosome. Specifically, splicing factor 1/branchpoint binding protein (SF1/BBP) is a single protein that can bind to the intronic branchpoint sequence (BPS), connecting 5’ and 3’ splice site binding complexes during early spliceosome assembly. The molecular function of this protein has been extensively investigated in yeast, metazoan and mammals. However, their counterparts in plants are seldomly reported. Results: Here, we conducted a systematic characterization of SF1 gene family across plant lineage. In this work, a total of 92 sequences from 59 plant species were identified. Phylogenetic relationships of these sequences were constructed and subsequent bioinformatic analysis suggested that this family is likely originated from an ancient gene transposition duplication event. Most plant species were shown to maintain a single copy of this gene. Furthermore, an additional RNA binding motif (RRM) existed in most members of this gene family in comparison to their animal and yeast counterparts, indicating their potential role conserved in plant lineage. Conclusion: Our comprehensive analysis presents general feature of gene and protein structure of this splicing factor family and will provide fundamental information for further functional studies in plants.

scholarly journals Structural basis of UCUU RNA motif recognition by splicing factor RBM20

2019 ◽  
Author(s):  
Santosh Kumar Upadhyay ◽  
Cameron D. Mackereth
Keyword(s):  
Heart Development ◽  
Rna Binding ◽  
Protein Isoforms ◽  
Splicing Factor ◽  
Common Element ◽  
Structural Basis ◽  
Binding Motif ◽  
Rna Recognition Motif ◽  
Rrm Domain ◽  
Rna Motif

ABSTRACTThe vertebrate splicing factor RBM20 (RNA Binding Motif protein 20) regulates protein isoforms important for heart development and function, with mutations in the gene linked to cardiomyopathy. Previous studies have identified the four base RNA motif UCUU as a common element in pre-mRNA targeted by RBM20. Here, we have determined the structure of the RNA Recognition Motif (RRM) domain from mouse RBM20 bound to RNA containing a UCUU sequence. The atomic details show that the RRM domain spans a larger region than initially proposed in order to interact with the complete UCUU motif, with a well-folded C-terminal helix encoded by exon 8 critical for high affinity binding. This helix only forms upon binding RNA with the final uracil, and removing the helix reduces affinity as well as specificity. We therefore find that RBM20 uses a coupled folding-binding mechanism by the C-terminal helix to specifically recognize the UCUU RNA motif.

scholarly journals New Insights in RBM20 Cardiomyopathy

2020 ◽  
Vol 17 (5) ◽  
pp. 234-246
Author(s):  
D. Lennermann ◽  
J. Backs ◽  
M. M. G. van den Hoogenhof
Keyword(s):  
Rna Binding ◽  
Severe Disease ◽  
Disease Onset ◽  
Splicing Factor ◽  
Calcium Handling ◽  
Binding Motif ◽  
Relative Contribution ◽  
Specific Manner ◽  
Male Patients ◽  
Gender Specific

Abstract Purpose of Review This review aims to give an update on recent findings related to the cardiac splicing factor RNA-binding motif protein 20 (RBM20) and RBM20 cardiomyopathy, a form of dilated cardiomyopathy caused by mutations in RBM20. Recent Findings While most research on RBM20 splicing targets has focused on titin (TTN), multiple studies over the last years have shown that other splicing targets of RBM20 including Ca2+/calmodulin-dependent kinase IIδ (CAMK2D) might be critically involved in the development of RBM20 cardiomyopathy. In this regard, loss of RBM20 causes an abnormal intracellular calcium handling, which may relate to the arrhythmogenic presentation of RBM20 cardiomyopathy. In addition, RBM20 presents clinically in a highly gender-specific manner, with male patients suffering from an earlier disease onset and a more severe disease progression. Summary Further research on RBM20, and treatment of RBM20 cardiomyopathy, will need to consider both the multitude and relative contribution of the different splicing targets and related pathways, as well as gender differences.

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