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The International Journal of... May 2019STAT3β is an isoform of STAT3 (signal transducer and activator of transcription 3) that differs from the STAT3α isoform by the replacement of the C-terminal 55 amino... (Review)
Review
STAT3β is an isoform of STAT3 (signal transducer and activator of transcription 3) that differs from the STAT3α isoform by the replacement of the C-terminal 55 amino acid residues with 7 specific residues. The constitutive activation of STAT3α plays a pivotal role in the activation of oncogenic pathways, such as cell proliferation, maturation and survival, while STAT3β is often referred to as a dominant-negative regulator of cancer. STAT3β reveals a "spongy cushion" effect through its cooperation with STAT3α or forms a ternary complex with other co-activators. Especially in tumour cells, relatively high levels of STAT3β lead to some favourable changes. However, there are still many mechanisms that have not been clearly explained in contrast to STAT3α, such as STAT3β nuclear retention, more stable heterodimers and the prolonged Y705 phosphorylation. In addition to its transcriptional activities, STAT3β may also function in the cytosol with respect to the mitochondria, cytoskeleton rearrangements and metastasis of cancer cells. In this review, we summarize the mechanisms that underlie the unique roles of STAT3β combined with total STAT3 to enlighten and draw the attention of researchers studying STAT3 and discuss some interesting questions that warrant answers.
Topics: Animals; Humans; Neoplasms; Protein Isoforms; STAT3 Transcription Factor
PubMed: 30822557
DOI: 10.1016/j.biocel.2019.02.006 -
European Journal of Medicinal Chemistry Aug 2022In the past few decades, the development of heat shock protein 90 (Hsp90) inhibitors for cancer treatment has not stopped. About twenty compounds have been evaluated in... (Review)
Review
In the past few decades, the development of heat shock protein 90 (Hsp90) inhibitors for cancer treatment has not stopped. About twenty compounds have been evaluated in the clinical trials, but the FDA approved none of them because of toxic effects and/or not enough efficacies. Insufficient isoform selectivity has been considered as one of the reasons for these failures recently. Therefore, developing isoform-selective Hsp90 inhibitors could probably make great progress in searching for therapeutic agents for cancer as well as many other diseases. Here, we summarized classic pan-inhibitors of Hsp90 based on the classification of binding sites and illustrated design strategies applied in the drug discovery. We summed up current isoform-specific Hsp90 inhibitors including their discovery processes and potential indications.
Topics: Antineoplastic Agents; Binding Sites; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Protein Isoforms
PubMed: 35691175
DOI: 10.1016/j.ejmech.2022.114516 -
IEEE/ACM Transactions on Computational... 2022Alternative splicing enables a gene spliced into different isoforms and hence protein variants. Identifying individual functions of these isoforms help deciphering the...
Alternative splicing enables a gene spliced into different isoforms and hence protein variants. Identifying individual functions of these isoforms help deciphering the functional diversity of proteins. Although much efforts have been made for automatic gene function prediction, few efforts have been moved toward computational isoform function prediction, mainly due to the unavailable (or scanty) functional annotations of isoforms. Existing efforts directly combine multiple RNA-seq datasets without account of the important tissue specificity of alternative splicing. To bridge this gap, we introduce a novel approach called TS-Isofun to predict the functions of isoforms by integrating multiple functional association networks with respect to tissue specificity. TS-Isofun first constructs tissue-specific isoform functional association networks using multiple RNA-seq datasets from tissue-wise. Next, TS-Isofun assigns weights to these networks and models the tissue specificity by selectively integrating them with adaptive weights. It then introduces a joint matrix factorization-based data fusion model to leverage the integrated network, gene-level data and functional annotations of genes to infer the functions of isoforms. To achieve coherent weight assignment and isoform function prediction, TS-Isofun jointly optimizes the weights of individual networks and the isoform function prediction in a unified objective function. Experimental results show that TS-Isofun significantly outperforms state-of-the-art methods and the account of tissue specificity contributes to more accurate isoform function prediction.
Topics: Alternative Splicing; Organ Specificity; Protein Isoforms
PubMed: 34185647
DOI: 10.1109/TCBB.2021.3093167 -
Trends in Cell Biology Apr 2023Our understanding of cancer and the key pathways that drive cancer survival has expanded rapidly over the past several decades. However, there are still important... (Review)
Review
Our understanding of cancer and the key pathways that drive cancer survival has expanded rapidly over the past several decades. However, there are still important challenges that continue to impair patient survival, including our inability to target cancer stem cells (CSCs), metastasis, and drug resistance. The transcription factor p63 is a p53 family member with multiple isoforms that carry out a wide array of functions. Here, we discuss the critical importance of the ΔNp63α isoform in cancer and potential therapeutic strategies to target ΔNp63α expression to impair the CSC population, as well as to prevent metastasis and drug resistance to improve patient survival.
Topics: Humans; Tumor Suppressor Proteins; Neoplasms; Transcription Factors; Protein Isoforms; Gene Expression Regulation, Neoplastic; Cell Line, Tumor
PubMed: 36115734
DOI: 10.1016/j.tcb.2022.08.003 -
Nucleic Acids Research Jul 2015This paper introduces the APPRIS WebServer (http://appris.bioinfo.cnio.es) and WebServices (http://apprisws.bioinfo.cnio.es). Both the web servers and the web services...
This paper introduces the APPRIS WebServer (http://appris.bioinfo.cnio.es) and WebServices (http://apprisws.bioinfo.cnio.es). Both the web servers and the web services are based around the APPRIS Database, a database that presently houses annotations of splice isoforms for five different vertebrate genomes. The APPRIS WebServer and WebServices provide access to the computational methods implemented in the APPRIS Database, while the APPRIS WebServices also allows retrieval of the annotations. The APPRIS WebServer and WebServices annotate splice isoforms with protein structural and functional features, and with data from cross-species alignments. In addition they can use the annotations of structure, function and conservation to select a single reference isoform for each protein-coding gene (the principal protein isoform). APPRIS principal isoforms have been shown to agree overwhelmingly with the main protein isoform detected in proteomics experiments. The APPRIS WebServer allows for the annotation of splice isoforms for individual genes, and provides a range of visual representations and tools to allow researchers to identify the likely effect of splicing events. The APPRIS WebServices permit users to generate annotations automatically in high throughput mode and to interrogate the annotations in the APPRIS Database. The APPRIS WebServices have been implemented using REST architecture to be flexible, modular and automatic.
Topics: Alternative Splicing; Animals; Cats; Cattle; Dogs; Humans; Internet; Mice; Molecular Sequence Annotation; Protein Isoforms; Rats; Software
PubMed: 25990727
DOI: 10.1093/nar/gkv512 -
European Journal of Immunology Jul 2023Ras GTPases, well characterized for their role in oncogenesis, are the cells' molecular switches that signal to maintain immune homeostasis through cellular development,... (Review)
Review
Ras GTPases, well characterized for their role in oncogenesis, are the cells' molecular switches that signal to maintain immune homeostasis through cellular development, proliferation, differentiation, survival, and apoptosis. In the immune system, T cells are the central players that cause autoimmunity if dysregulated. Antigen-specific T-cell receptor (TCR) stimulation activates Ras-isoforms, which exhibit isoform-specific activator and effector requirements, functional specificities, and a selective role in T-cell development and differentiation. Recent studies show the role of Ras in T-cell-mediated autoimmune diseases; however, there is a scarcity of knowledge about the role of Ras in T-cell development and differentiation. To date, limited studies have demonstrated Ras activation in response to positive and negative selection signals and Ras isoform-specific signaling, including subcellular signaling, in immune cells. The knowledge of isoform-specific functions of Ras in T cells is essential, but still inadequate to develop the T-cell-targeted Ras isoform-specific treatment strategies for the diseases caused by altered Ras-isoform expression and activation in T cells. In this review, we discuss the role of Ras in T-cell development and differentiation, critically analyzing the isoform-specific functions.
Topics: Humans; T-Lymphocytes; Signal Transduction; Cell Differentiation; Receptors, Antigen, T-Cell; Protein Isoforms; Autoimmune Diseases
PubMed: 37173132
DOI: 10.1002/eji.202350430 -
IEEE/ACM Transactions on Computational... 2022Alternative splicing enables a gene translating into different isoforms and into the corresponding proteoforms, which actually accomplish various biological functions of...
Alternative splicing enables a gene translating into different isoforms and into the corresponding proteoforms, which actually accomplish various biological functions of a living body. Isoform-isoform interactions (IIIs) provide a higher resolution interactome to explore the cellular processes and disease mechanisms than the canonically studied protein-protein interactions (PPIs), which are often recorded at the coarse gene level. The knowledge of IIIs is critical to map pathways, understand protein complexity and functional diversity, but the known IIIs are very scanty. In this paper, we propose a deep learning based method called DeepIII to systematically predict genome-wide IIIs by integrating diverse data sources, including RNA-seq datasets of different human tissues, exon array data, domain-domain interactions (DDIs) of proteins, nucleotide sequences and amino acid sequences. Particularly, DeepIII fuses these data to learn the representation of isoform pairs with a four-layer deep neural networks, and then performs binary classification on the learnt representation to achieve the prediction of IIIs. Experimental results show that DeepIII achieves a superior prediction performance to the state-of-the-art solutions and the III network constructed by DeepIII gives more accurate isoform function prediction. Case studies further confirm that DeepIII can differentiate the individual interaction partners of different isoforms spliced from the same gene. The code and datasets of DeepIII are available at http://mlda.swu.edu.cn/codes.php?name=DeepIII.
Topics: Alternative Splicing; Humans; Neural Networks, Computer; Protein Isoforms
PubMed: 33764878
DOI: 10.1109/TCBB.2021.3068875 -
International Journal of Molecular... Jun 2023Over the past 8 years, multiple studies examined the phenomenon of isoform switching in human cancers and discovered that isoform switching is widespread, with hundreds...
Over the past 8 years, multiple studies examined the phenomenon of isoform switching in human cancers and discovered that isoform switching is widespread, with hundreds to thousands of such events per cancer type. Although all of these studies used slightly different definitions of isoform switching, which in part led to a rather poor overlap of their results, they all leveraged transcript usage, a proportion of the transcript's expression in the total expression level of the parent gene, to detect isoform switching. However, how changes in transcript usage correlate with changes in transcript expression is not sufficiently explored. In this article, we adopt the most common definition of isoform switching and use a state-of-the-art tool for the analysis of differential transcript usage, SatuRn, to detect isoform switching events in 12 cancer types. We analyze the detected events in terms of changes in transcript usage and the relationship between transcript usage and transcript expression on a global scale. The results of our analysis suggest that the relationship between changes in transcript usage and changes in transcript expression is far from straightforward, and that such quantitative information can be effectively used for prioritizing isoform switching events for downstream analyses.
Topics: Humans; Alternative Splicing; Gene Expression Profiling; Protein Isoforms; Neoplasms
PubMed: 37373214
DOI: 10.3390/ijms241210065 -
The FEBS Journal Dec 2023Notch receptor activation is regulated by the intramembrane protease γ-secretase, which cleaves and liberates the Notch intracellular domain (Nicd) that regulates gene...
Notch receptor activation is regulated by the intramembrane protease γ-secretase, which cleaves and liberates the Notch intracellular domain (Nicd) that regulates gene transcription. While γ-secretase cleavage is necessary, we demonstrate it is insufficient for Notch activation and requires vesicular trafficking. Here, we report Divalent metal transporter 1 (Dmt1, Slc11A2) as a novel and essential regulator of Notch signalling. Dmt1-deficient cells are defective in Notch signalling and have perturbed endolysosomal trafficking and function. Dmt1 encodes for two isoforms, with and without an iron response element (ire). We show that isoform-specific silencing of Dmt1-ire and Dmt1+ire has opposite consequences on Notch-dependent cell fates in cell lines and intestinal organoids. Loss of Dmt1-ire suppresses Notch activation and promotes differentiation, whereas loss of Dmt1+ire causes Notch activation and maintains stem-progenitor cell fates. Dmt1 isoform expression correlates with Notch and Wnt signalling in Apc-deficient intestinal organoids and human colorectal cancers. Consistently, Dmt1-ire silencing induces Notch-dependent differentiation in colorectal cancer cells. These data identify Dmt1 isoforms as binary switches controlling Notch cell fate decisions in normal and tumour cells.
Topics: Humans; Amyloid Precursor Protein Secretases; Cell Line; Iron; Iron-Binding Proteins; Protein Isoforms; Cation Transport Proteins; Regulatory Sequences, Nucleic Acid
PubMed: 37646174
DOI: 10.1111/febs.16946 -
Clinical Epigenetics 2016DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC), is considered to be one of the principal interfaces between the genome and our... (Review)
Review
DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC), is considered to be one of the principal interfaces between the genome and our environment, and it helps explain phenotypic variations in human populations. Initial reports of large differences in methylation level in genomic regulatory regions, coupled with clear gene expression data in both imprinted genes and malignant diseases, provided easily dissected molecular mechanisms for switching genes on or off. However, a more subtle process is becoming evident, where small (<10 %) changes to intermediate methylation levels are associated with complex disease phenotypes. This has resulted in two clear methylation paradigms. The latter "subtle change" paradigm is rapidly becoming the epigenetic hallmark of complex disease phenotypes, although we are currently hampered by a lack of data addressing the true biological significance and meaning of these small differences. Our initial expectation of rapidly identifying mechanisms linking environmental exposure to a disease phenotype led to numerous observational/association studies being performed. Although this expectation remains unmet, there is now a growing body of literature on specific genes, suggesting wide ranging transcriptional and translational consequences of such subtle methylation changes. Data from the glucocorticoid receptor (NR3C1) has shown that a complex interplay between DNA methylation, extensive 5'UTR splicing, and microvariability gives rise to the overall level and relative distribution of total and N-terminal protein isoforms generated. Additionally, the presence of multiple AUG translation initiation codons throughout the complete, processed mRNA enables translation variability, hereby enhancing the translational isoforms and the resulting protein isoform diversity, providing a clear link between small changes in DNA methylation and significant changes in protein isoforms and cellular locations. Methylation changes in the NR3C1 CpG island alters the NR3C1 transcription and eventually protein isoforms in the tissues, resulting in subtle but visible physiological variability. This review addresses the current pathophysiological and clinical associations of such characteristically small DNA methylation changes, the ever-growing roles of DNA methylation and the evidence available, particularly from the glucocorticoid receptor of the cascade of events initiated by such subtle methylation changes, as well as addressing the underlying question as to what represents a genuine biologically significant difference in methylation.
Topics: 5' Untranslated Regions; 5-Methylcytosine; CpG Islands; DNA Methylation; Environmental Exposure; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Phenotype; Protein Isoforms; Receptors, Glucocorticoid
PubMed: 27602172
DOI: 10.1186/s13148-016-0256-8