scholarly journals Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 760 ◽  
Author(s):  
Silvia Belluti ◽  
Giovanna Rigillo ◽  
Carol Imbriano
Keyword(s):  
Transcription Factors ◽  
Alternative Splicing ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Regulatory Elements ◽  
Apoptosis Resistance ◽  
Clinical Biomarkers ◽  
Differentiation Block ◽  
Dna Regulatory Elements

Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

scholarly journals Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma

2018 ◽  
Vol 19 (10) ◽  
pp. 3272 ◽  
Author(s):  
Manel Benhassine ◽  
Sylvain Guérin
Keyword(s):  
Transcription Factors ◽  
Uveal Melanoma ◽  
Serotonin Receptor ◽  
Molecular Mechanisms ◽  
Regulatory Region ◽  
Gene Signature ◽  
Regulatory Elements ◽  
Gene Encoding ◽  
Aberrant Expression ◽  
Factor I

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B− but not in HTR23B+ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

scholarly journals Regulation of TEAD Transcription Factors in Cancer Biology

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 600 ◽  
Author(s):  
Hyunbin Huh ◽  
Dong Kim ◽  
Han-Sol Jeong ◽  
Hyun Park
Keyword(s):  
Transcription Factors ◽  
Growth Factor ◽  
Tumor Progression ◽  
Transforming Growth Factor Beta ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Transforming Growth Factor ◽  
Clinicopathological Parameters ◽  
Transcriptional Output

Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics.

Evidence of the modulation of mRNA splicing fidelity in humans by oxidative stress and p53

Genome ◽  
2007 ◽  
Vol 50 (10) ◽  
pp. 946-953 ◽  
Author(s):  
Kim Disher ◽  
Adonis Skandalis
Keyword(s):  
Oxidative Stress ◽  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Dna Lesions ◽  
Mrna Splicing ◽  
Aberrant Splice ◽  
Biological Phenomenon ◽  
Mrna Splice ◽  
Human Genes

The majority of human genes generate mRNA splice variants and while there is little doubt that alternative splicing is an important biological phenomenon, it has also become apparent that some splice variants are associated with disease. To elucidate the molecular mechanisms responsible for generating aberrant splice variants, we have investigated alternative splicing of the human genes HPRT and POLB following oxidative stress in different genetic backgrounds. Our study revealed that splicing fidelity is sensitive to oxidative stress. Following treatment of cells with H2O2, the overall frequency of aberrant, unproductive splice variants increased in both loci. At least in POLB, splicing fidelity is p53 dependent. In the absence of p53, the frequency of POLB splice variants is elevated but oxidative stress does not further increase the frequency of splice variants. Our data indicate that mis-splicing following oxidative stress represents a novel and significant genotoxic outcome and that it is not simply DNA lesions induced by oxidative stress that lead to mis-splicing but changes in the alternative splicing machinery itself.

scholarly journals Plenary Lecture 2 Transcription factors, regulatory elements and nutrient–gene communication

2009 ◽  
Vol 69 (1) ◽  
pp. 91-94 ◽  
Author(s):  
Robert J. Cousins ◽  
Tolunay B. Aydemir ◽  
Louis A. Lichten
Keyword(s):  
Transcription Factors ◽  
Histone Acetylation ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Gene Activation ◽  
Regulatory Elements ◽  
Atp Citrate Lyase ◽  
Signalling Molecules ◽  
Citrate Lyase ◽  
Normal Metabolism

Dramatic advances have been made in the understanding of the differing molecular mechanisms used by nutrients to regulate genes that are essential for their biological roles to carry out normal metabolism. Classical studies have focused on nutrients as ligands to activate specific transcription factors. New interest has focused on histone acetylation as a process for either global or limited gene activation and is the first mechanism to be discussed. Nuclear ATP-citrate lyase generates acetyl-CoA, which has been shown to have a role in the activation of specific genes via selective histone acetylation. Transcription factor acetylation may provide a second mode of control of nutrient-responsive gene transcription. The third mechanism relates to the availability of response elements within chromatin, which as well as the location of the elements in the gene may allow or prevent transcription. A fourth mechanism involves intracellular transport of Zn ions, which can orchestrate localized enzyme inhibition–activation. This process in turn influences signalling molecules that regulate gene expression. The examples provided in the present review point to a new level of complexity in understanding nutrient–gene communication.

scholarly journals Genome-Wide Identification and Characterization of bHLH Transcription Factors Related to Anthocyanin Biosynthesis in Red Walnut (Juglans regia L.)

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Zhao ◽  
Yonghui Liu ◽  
Lin Li ◽  
Haijun Meng ◽  
Ying Yang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Family ◽  
Developmental Stage ◽  
Molecular Mechanisms ◽  
Anthocyanin Biosynthesis ◽  
Expression Profiles ◽  
Juglans Regia ◽  
Expression Patterns ◽  
Regulatory Elements

Basic helix-loop-helix (bHLH) proteins are transcription factors (TFs) that have been shown to regulate anthocyanin biosynthesis in many plant species. However, the bHLH gene family in walnut (Juglans regia L.) has not yet been reported. In this study, 102 bHLH genes were identified in the walnut genome and were classified into 15 subfamilies according to sequence similarity and phylogenetic relationships. The gene structure, conserved domains, and chromosome location of the genes were analyzed by bioinformatic methods. Gene duplication analyses revealed that 42 JrbHLHs were involved in the expansion of the walnut bHLH gene family. We also characterized cis-regulatory elements of these genes and performed Gene Ontology enrichment analysis of gene functions, and examined protein-protein interactions. Four candidate genes (JrEGL1a, JrEGL1b, JrbHLHA1, and JrbHLHA2) were found to have high homology to genes encoding bHLH TFs involved in anthocyanin biosynthesis in other plants. RNA sequencing revealed tissue- and developmental stage-specific expression profiles and distinct expression patterns of JrbHLHs according to phenotype (red vs. green leaves) and developmental stage in red walnut hybrid progeny, which were confirmed by quantitative real-time PCR analysis. All four of the candidate JrbHLH proteins localized to the nucleus, consistent with a TF function. These results provide a basis for the functional characterization of bHLH genes and investigations on the molecular mechanisms of anthocyanin biosynthesis in red walnut.

scholarly journals Nuclear receptors and chromatin: an inducible couple

2013 ◽  
Vol 52 (2) ◽  
pp. R137-R149 ◽  
Author(s):  
Raffaella Maria Gadaleta ◽  
Luca Magnani
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Structural Changes ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Epigenetic Modifications ◽  
Non Coding Rna ◽  
Transcriptional Machinery ◽  
Dna Regulatory Elements

The nuclear receptor (NR) family comprises 48 transcription factors (TFs) with essential and diverse roles in development, metabolism and disease. Differently from other TFs, NRs engage with well-defined DNA-regulatory elements, mostly after ligand-induced structural changes. However, NR binding is not stochastic, and only a fraction of the cognate regulatory elements within the genome actively engage with NRs. In this review, we summarize recent advances in the understanding of the interactions between NRs and DNA. We discuss how chromatin accessibility and epigenetic modifications contribute to the recruitment and transactivation of NRs. Lastly, we present novel evidence of the interplay between non-coding RNA and NRs in the mediation of the assembly of the transcriptional machinery.

scholarly journals TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii11-ii11
Author(s):  
Daisuke Kawauchi ◽  
Kristian Pajtler ◽  
Yiju Wei ◽  
Konstantin Okonechnikov ◽  
Patricia Silva ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Site ◽  
Nuclear Localization ◽  
Molecular Mechanisms ◽  
Regulatory Elements ◽  
Molecular Characteristics ◽  
Independent Manner ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Localization Signal ◽  
Oncogenic Driver

Abstract YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

BRCA1 exon 11 alternative splicing, multiple functions and the association with cancer

2012 ◽  
Vol 40 (4) ◽  
pp. 768-772 ◽  
Author(s):  
Claudia Tammaro ◽  
Michela Raponi ◽  
David I. Wilson ◽  
Diana Baralle
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Cancer Biology ◽  
Mammary Epithelial Cells ◽  
Splice Variants ◽  
Mammary Epithelial ◽  
Cell Phenotype ◽  
Exon 11 ◽  
The Impact ◽  
Brca1 Exon

BRCA1 (breast cancer early-onset 1) alternative splicing levels are regulated in a cell-cycle- and cell-type-specific manner, with splice variants being present in different proportions in tumour cell lines as well as in normal mammary epithelial cells. The importance of this difference in the pathogenesis of breast cancer has yet to be determined. Developing an understanding of the impact of BRCA1 isoform ratio changes on cell phenotype will be of value in breast cancer and may offer therapeutic options. In the present paper, we describe the splicing isoforms of BRCA1 exon 11, their possible role in cancer biology and the importance of maintaining a balanced ratio.

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