Resveratrol, by Modulating RNA Processing Factor Levels, Can Influence the Alternative Splicing of Pre-mRNAs (original) (raw)
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Frontiers in Cell and Developmental Biology
There have been significant advances, particularly over the last 20 years, in the identification of non-coding RNAs (ncRNAs) and their pathophysiological role in a wide range of disease states, particularly cancer and other chronic conditions characterized by excess inflammation and oxidative stress such as atherosclerosis, diabetes, obesity, multiple sclerosis, osteoporosis, liver and lung fibrosis. Such discoveries have potential therapeutic implications as a better understanding of the molecular mechanisms underpinning the effects of ncRNAs on critical homeostatic control mechanisms and biochemical pathways might lead to the identification of novel druggable targets. In this context, increasing evidence suggests that several natural compounds can target ncRNAs at different levels and, consequently, influence processes involved in the onset and progression of disease states. The natural phenol resveratrol has been extensively studied for therapeutic purposes in view of its establi...
BMC cell biology, 2017
Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence. Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena wer...
Modulation of RNA splicing as a potential treatment for cancer
Bioengineered Bugs, 2011
C lose to 90% of human genes are transcribed into pre-mRNA that undergoes alternative splicing, producing multiple mRNAs and proteins from single genes. This process is largely responsible for human proteome diversity, and about half of genetic disease-causing mutations affect splicing. Splice-switching oligonucleotides (SSOs) comprise an emerging class of antisense therapeutics that modify gene expression by directing pre-mRNA splice site usage. Bauman et al. investigated an SSO that upregulated the expression of an anti-cancer splice variant while simultaneously eliminating an overexpressed cancer-causing splice variant. This was accomplished by targeting pre-mRNA of the apoptotic regulator Bcl-x, which is alternatively spliced to express antiand pro-apoptotic splice variants Bcl-x L and Bcl-x S , respectively. High expression of Bcl-x L is a hallmark of many cancers and is considered a general mechanism used by cancer cells to evade apoptosis. Redirection of Bcl-x pre-mRNA splicing from Bcl-x L to-x S by SSO induced apoptotic and chemosensitizing effects in various cancer cell lines. Importantly, the paper shows that delivery of Bcl-x SSO using a lipid nanoparticle redirected Bcl-x splicing and reduced tumor burden in melanoma lung metastases. This was the first demonstration of SSO efficacy in tumors in vivo. SSOs are not limited to be solely potential anti-cancer drugs. SSOs were first applied to repair aberrant splicing in thalassemia, a genetic disease, they have been used to create novel proteins (e.g., Δ7TNFR1), and they have recently progressed to clinical trials for patients with Duchenne muscular dystrophy.
Molecular Immunology, 2010
The present study shows for the first time that the polyphenol resveratrol (RESV) blocks processing of tumour necrosis factor-␣ (TNF-␣) pre-mRNA in mature mRNA. This study was carried out in turbot (Psetta maxima (L.)), a fish species that we are using to evaluate the effects of RESV on the inflammatory response in vertebrates. Treatment of turbot head kidney leucocytes with polysaccharides from the seaweed Ulva rigida (ulvan) resulted in an increase in TNF-␣ expression. RESV did not inhibit transcription but almost completely inhibited the production of mRNA in ulvan-induced cells and caused a notable increase in the level of unspliced TNF-␣ pre-mRNA. RESV also induced accumulation of IL-1 pre-mRNA at the expense of mature mRNA, although the effects on IL-1 were less evident than those on TNF-␣. However, the housekeeping gene was not affected by RESV. We also evaluated the effects of RESV in vivo under an inflammatory stimulus and found an inhibitory effect on TNF-␣ and IL-1 pre-mRNA splicing in turbot head kidney at 24 and 48 h post-injection. In addition, RESV also reduced migration of cells to the peritoneal cavity under the same inflammatory stimulus. The results show that this fish species may be a useful model for analysing the effects of RESV on TNF-␣ and IL-1 expression, and suggest that RESV could be used to decrease the levels of pro-inflammatory cytokines in vivo and to reduce inflammatory reactions in certain inflammatory diseases.
Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment
BioMed Research International, 2016
In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types...
Journal of Traditional and Complementary Medicine, 2020
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Pre-mRNA splicing in disease and therapeutics
Trends in Molecular Medicine, 2012
In metazoans, alternative splicing of genes is essential for regulating gene expression and contributing to functional complexity. Computational predictions, comparative genomics, and transcriptome profiling of normal and diseased tissues indicate an unexpectedly high fraction of diseases are caused by mutations that alter splicing. Mutations in cis elements cause mis-splicing of genes that alter gene function and contribute to disease pathology. Mutations of core spliceosomal factors are associated with hematolymphoid neoplasias, retinitis pigmentosa, and microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Mutations in the trans regulatory factors that control alternative splicing are associated with autism spectrum disorder, amyotrophic lateral sclerosis (ALS), and various cancers. In addition to discussing the disorders caused by these mutations, this review summarizes therapeutic approaches that have emerged to correct splicing of individual genes or target the splicing machinery.
Current Gene Therapy, 2005
Antisense oligonucleotides initially offered great hope as specific compounds to modify gene expression, primarily through RNaseH induced degradation of the target transcript. Expansion of the field led to new chemistries capable of invoking different mechanisms, including suppression of protein synthesis by translational blockade, and there is now a major interest in downregulation of gene expression using short interfering RNAs to induce RNA silencing. Naturally occurring microRNAs have been implicated in the regulation of gene expression. This review considers examples of antisense oligonucleotides redirecting the process of exon recognition and intron removal during gene transcript splicing. While suppression of gene expression is necessary to address some conditions, it appears likely that there may be many more clinical applications for antisense oligonucleotides in redirecting splicing patterns. Pre-mRNA splicing is a tightly coordinated , multifactorial process, which can be disrupted by antisense oligonucleotides in a highly specific manner, allowing either suppression of aberrant splicing, bypass of nonsense or frame-shifting mutations or alteration of spliceoform ratios. Manipulation of splicing patterns has been applied to a diverse range of conditions, including β-thalassemia, Duchenne muscular dystrophy, spinal muscular atrophy and certain cancers. Alternative exon usage has been identified as a major mechanism for generating diversity from a limited repertoire of genes in higher eukaryotes. Considering that up to 75% of all human primary gene transcripts are reported to be alternatively spliced, intervention at the level of pre-mRNA processing is likely to become increasingly significant in the fight against genetic and acquired disorders.
Alternative splicing isoforms in health and disease
Pflugers Archiv : European journal of physiology, 2018
Alternative splicing (AS) of protein-coding messenger RNAs is an essential regulatory mechanism in eukaryotic gene expression that controls the proper function of proteins. It is also implicated in the physiological regulation of mitochondria and various ion channels. Considering that mis-splicing can result in various human diseases by modifying or abrogating important physiological protein functions, a fine-tuned balance of AS is essential for human health. Accumulated data highlight the importance of alternatively spliced isoforms in various diseases, including neurodegenerative disorders, cancer, immune and infectious diseases, cardiovascular diseases, and metabolic conditions. However, basic understanding of disease mechanisms and development of clinical applications still require the integration and interpretation of physiological roles of AS. This review discusses the roles of AS in health and various diseases, while highlighting potential AS-targeting therapeutic applications.