scholarly journals HMGA1 zebrafish co-orthologue hmga1b can modulate p53-dependent cellular responses but is unable to control the alternative splicing of psen1

2018 ◽  
Author(s):  
Seyed Hani Moussavi Nik ◽  
Morgan Newman ◽  
Amanda Lumsden ◽  
Tanya Jayne ◽  
Michael Lardelli
Keyword(s):  
Alternative Splicing ◽  
High Mobility ◽  
Cellular Responses ◽  
Chromatin Binding ◽  
Low Oxygen ◽  
Over Expression ◽  
Protein Isoform ◽  
Stress Dependent ◽  
Nascent Transcripts ◽  
Cancerous Cells

ABSTRACTThe HIGH MOBILITY GROUP AT-HOOK 1 (HMGA1) family of chromatin-binding proteins plays important roles in cellular responses to low oxygen. HMGA1 proteins regulate gene activity both in the nucleus and within mitochondria. They are expressed mainly during embryogenesis and their upregulation in cancerous cells indicates poor prognosis. The human HMGA1a isoform is upregulated under hypoxia via oxidative stress-dependent signalling and can then bind nascent transcripts of the familial Alzheimer’s disease gene PSEN2 to regulate alternative splicing to produce the truncated PSEN2 protein isoform PS2V. Zebrafish where hmga1a expression is induced by hypoxia to control splicing of the psen1 gene to produce the PS2V-equivalent isoform PS1IV. Zebrafish possess a second gene with apparent HMGA1 orthology, hmga1b. Here we investigate the predicted structure of Hmga1b protein and demonstrate it to be co-orthologous to human HMGA1 and most similar in structure to human isoform HMGA1c. We show that forced over-expression of either hmga1a or hmga1b mRNA can suppress the action of the cytotoxin hydroxyurea in stimulating cell death and transcription of the genes mdm2 and cdkn1a that, in humans, are controlled by p53. Our experimental data support an important role for HMGA1 proteins in modulation of p53-dependent responses and illuminate the evolutionary subfunctionalisation.

scholarly journals The Immune Tolerance Role of the HMGB1-RAGE Axis

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 564
Author(s):  
Haruki Watanabe ◽  
Myoungsun Son
Keyword(s):  
Immune Responses ◽  
Immune Tolerance ◽  
Lupus Erythematosus ◽  
Advanced Glycation Endproducts ◽  
High Mobility ◽  
Chromatin Binding ◽  
Advanced Glycation ◽  
Glycation Endproducts ◽  
Extracellular Milieu

The disruption of the immune tolerance induces autoimmunity such as systemic lupus erythematosus and vasculitis. A chromatin-binding non-histone protein, high mobility group box 1 (HMGB1), is released from the nucleus to the extracellular milieu in particular environments such as autoimmunity, sepsis and hypoxia. Extracellular HMGB1 engages pattern recognition receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE). While the HMGB1-RAGE axis drives inflammation in various diseases, recent studies also focus on the anti-inflammatory effects of HMGB1 and RAGE. This review discusses current perspectives on HMGB1 and RAGE’s roles in controlling inflammation and immune tolerance. We also suggest how RAGE heterodimers responding microenvironments functions in immune responses.

scholarly journals SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alyssa E. Johnson ◽  
Brian O. Orr ◽  
Richard D. Fetter ◽  
Armen J. Moughamian ◽  
Logan A. Primeaux ◽  
...  
Keyword(s):  
Dynamic Stability ◽  
Muscle Wasting ◽  
Dependent Manner ◽  
Missense Mutations ◽  
Over Expression ◽  
System A ◽  
Molecular Determinant ◽  
Intracellular Organelles ◽  
Stress Dependent ◽  
Lateral Sclerosis

AbstractMissense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson’s disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal–lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.

Alternative splicing deregulation leads to over expression of exon 13 P73 isoforms

2003 ◽  
Vol 2 (1) ◽  
pp. 163
Author(s):  
E. Lianos ◽  
D. Delakas ◽  
D. Arvanitis ◽  
D. Spandidos
Keyword(s):  
Alternative Splicing ◽  
Over Expression

scholarly journals Apoptotic endonuclease EndoG regulates alternative splicing of human telomerase catalytic subunit hTERT

2016 ◽  
Vol 62 (5) ◽  
pp. 544-554 ◽  
Author(s):  
D.D. Zhdanov ◽  
D.A. Vasina ◽  
E.V. Orlova ◽  
V.S. Orlova ◽  
M.V. Pokrovskaya ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Telomerase Activity ◽  
Catalytic Subunit ◽  
Over Expression ◽  
Htert Gene ◽  
Template Strand ◽  
Non Coding Rna ◽  
Dna Strand ◽  
Human Telomerase ◽  
Long Non Coding Rna

Human telomerase catalytic subunit hTERT is subjected to alternative splicing results in loss of its function and leads to decrease of telomerase activity. However, very little is known about the mechanism of hTERT pre-mRNA alternative splicing. Apoptotic endonuclease EndoG is known to participate this process. The aim of this study was to determine the role of EndoG in regulation of hTERT alternative splicing. Increased expression of b-deletion splice variant was determined during EndoG over-expression in CaCo-2 cell line, after EndoG treatment of cell cytoplasm and nuclei and after nuclei incubation with EndoG digested cell RNA. hTERT alternative splicing was induced by 47-mer RNA oligonucleotide in naked nuclei and in cells after transfection. Identified long non-coding RNA, that is the precursor of 47-mer RNA oligonucleotide. Its size is 1754 nucleotides. Based on the results the following mechanism was proposed. hTERT pre-mRNA is transcribed from coding DNA strand while long non-coding RNA is transcribed from template strand of hTERT gene. EndoG digests long non-coding RNA and produces 47-mer RNA oligonucleotide complementary to hTERT pre-mRNA exon 8 and intron 8 junction place. Interaction of 47-mer RNA oligonucleotide and hTERT pre-mRNA causes alternative splicing.

scholarly journals The dynamics of HMG protein–chromatin interactions in living cellsThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 87 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Gabi Gerlitz ◽  
Robert Hock ◽  
Tetsuya Ueda ◽  
Michael Bustin
Keyword(s):  
Binding Sites ◽  
Binding Proteins ◽  
Peer Review Process ◽  
High Mobility ◽  
Structural Features ◽  
Chromatin Binding ◽  
Hmg Proteins ◽  
Chromatin Dynamics ◽  
Chromatin Interactions ◽  
Major Factors

The dynamic interaction between nuclear proteins and chromatin leads to the functional plasticity necessary to mount adequate responses to regulatory signals. Here, we review the factors regulating the chromatin interactions of the high mobility group proteins (HMGs), an abundant and ubiquitous superfamily of chromatin-binding proteins in living cells. HMGs are highly mobile and interact with the chromatin fiber in a highly dynamic fashion, as part of a protein network. The major factors that affect the binding of HMGs to chromatin are operative at the level of the single nucleosome. These factors include structural features of the HMGs, competition with other chromatin-binding proteins for nucleosome binding sites, complex formation with protein partners, and post-translational modifications in the protein or in the chromatin-binding sites. The versatile modulation of the interaction between HMG proteins and chromatin plays a role in processes that establish the cellular phenotype.

scholarly journals Alternative splicing of RNAs transcribed from the human c-myb gene.

1990 ◽  
Vol 10 (6) ◽  
pp. 2715-2722 ◽  
Author(s):  
G L Shen-Ong ◽  
R M Skurla ◽  
J D Owens ◽  
J F Mushinski
Keyword(s):  
Alternative Splicing ◽  
Avian Myeloblastosis Virus ◽  
Alternative Transcripts ◽  
Myb Gene ◽  
Alternatively Spliced ◽  
Protein Isoform ◽  
Myb Protein ◽  
Myb Proteins ◽  
Carboxy Terminal ◽  
Novel Exon

An alternative splicing event in which a portion of the intron bounded by the vE6 and vE7 exons with v-myb homology is included as an additional 363-nucleotide coding exon (termed E6A or coding exon 9A) has been described for normal and tumor murine cells that express myb. We show here that this alternative splicing event is conserved in human c-myb transcripts. In addition, another novel exon (termed E7A or coding exon 10A) is identified in human c-myb mRNAs expressed in normal and tumor cells. Although the myb protein isoform encoded by murine E6A-containing mRNA is larger than the major c-myb protein, the predicted products of both forms of human alternatively spliced myb transcripts are 3'-truncated myb proteins that terminate in the alternative exons. These proteins are predicted to lack the same carboxy-terminal domains as the viral myb proteins encoded by avian myeloblastosis virus and E26 virus. The junction sequences that flank these exons closely resemble the consensus splice donor and splice acceptor sequences, yet the alternative transcripts are less abundant than is the major form of c-myb transcripts. The contribution that alternative splicing events in c-myb expression may make on c-myb function remains to be elucidated.

scholarly journals Microarray data analysis, structure prediction and in silico docking of drugs for inhibiting the over expression of High Mobility Group A1 in human malignant neoplasias

2020 ◽  
pp. 448-456
Author(s):  
Manish Devgun ◽  
Sukhbir Lal
Keyword(s):  
Data Analysis ◽  
Microarray Data ◽  
Structure Prediction ◽  
High Mobility ◽  
High Mobility Group ◽  
Microarray Data Analysis ◽  
Ramachandran Plot ◽  
Loop Optimization ◽  
In Silico Docking ◽  
Over Expression

The High Mobility Group A1 (HMGA1) gene over expression has been widely observed in various types of cancers. The raw data for microarray data analysis was obtained from the dataset record GDS3525. The SOM and K-means of the Genesis led to the identification of two clusters (each consisting of 30 genes) bearing HMGA1 gene. This on further analysis resulted into identification of 14 similar genes by Easy M-A. The evolutionary similarity of HMGA1 and GORASP2 is clearly observed in the Phylogenetic Tree. Due to the absence of precise structures, the homology modeling was done by using EasyModeller and the resulting models of proteins HMGA1 and GORASP2 were validated by Ramachandran plot. These models were further put to loop optimization by Modloop and the output models were assessed by Ramachandran plot (Rampage) and through SAVS (Procheck). The molecular docking was done by using Autodock, this resulted in two ligands, DB11641 (Vinflunine) and DB12674 (Lurbinectedin), showing potential for the effective treatment of various types of cancers characterized by the over expression of HMGA1 and GORASP2.

scholarly journals AUGmenting the proteome: Novel initiation codons and their role in protein isoform generation

2015 ◽  
Vol 37 (2) ◽  
pp. 19-23
Author(s):  
Mark J. Coldwell ◽  
Joanne L. Cowan
Keyword(s):  
Alternative Splicing ◽  
Translation Initiation ◽  
Messenger Rna ◽  
Genetic Material ◽  
Protein Sequencing ◽  
Protein Isoforms ◽  
Alternative Promoters ◽  
Alternative Translation ◽  
Initial Hypothesis ◽  
Protein Isoform

As the field of molecular biology developed, and the understanding of how inherited genetic material results in the expression of proteins was established, the initial hypothesis was that one gene gave rise to one protein1. As researchers delved deeper into the organization of the genetic code and advances in messenger RNA (mRNA) and protein sequencing were subsequently made, it has become abundantly clear that multiple mechanisms exist meaning that many mRNAs encode more than one version of a protein. Although alternative promoters and alternative splicing play a considerable role in the generation of protein isoforms, in this article we discuss how usage of alternative translation initiation codons in eukaryotes can also lead to an expanded proteome.

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