MicroRNA Member TaMIR5062 in T. Aestivum Involves Plant Drought and Salt Acclimation via Regulating Physiological Processes Associated with Water Retention and ROS Homeostasis

Abstract microRNA members negatively regulate target genes via posttranscriptional cleavage or translation repression mechanisms, impacting on plant growth, development, and stress response. In this study, we characterized TaMIR5062, a miRNA member in T. aestivum, in mediating drought and salt responses. TaMIR5062 interacts with six target genes, including two encoding calmodulins, three coding for 4-oxalocrotonate tautomerases, and one for pumilio-family RNA binding domain protein. The TaMIR5062 transcripts were gradually upregulated in plants upon 27-h drought and salt treatments, whose induced expression under stress treatments was restored following the normal recovery condition. Tobacco (N. tabacum) lines transformed with TaMIR5062 modified growth traits under drought and salt treatments; the lines overexpressing miRNA (i.e., Sen 1 and Sen 2) improved growth traits (i.e., biomass, leaf area, and root length) whereas those with knockdown (Anti 1) alleviated growth features compared with wild type. These results suggested the critical role of TaMIR5062 in improving plant drought and salt tolerance. In line with growth traits in stress-challenged lines, improved leaf water retention (i.e., promoted stomata closing, water losing rate, and osmolytes) and ROS-associated parameters (higher SOD, CAT, and POD activities, etc.) were shown in Sen 1 and Sen 2 under stress conditions. Antioxidant enzyme (AE) genes NtMnSOD1, NtCAT, and NtPOD9 encoding SOD, CAT, and POD, respectively, enhanced transcription in Sen 1 and downregulated expression in Anti 1 challenged with drought and salt stress. These results suggested the improved ROS homeostasis mediated by TaMIR5062 associates modified expression of distinct AE genes. Quantities of genes functional into categories “biological process”, “cellular component”, and “molecular function” contribute to TaMIR5062-mediated osmotic stress adaptation by regulating distinct biological pathways (i.e., protein folding) and metabolisms (i.e., photosynthesis and isoprenoid biosynthesis), which impact on plant osmotic-regulation, ROS homeostasis, and stress defensiveness underlying miRNA regulation. TaMIR5062 is a valuable target for molecular breeding of drought-tolerant crop cultivars.

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Mechanisms of transcriptional regulation by WT1 (Wilms’ tumour 1)

Biochemical Journal ◽

10.1042/bj20131587 ◽

2014 ◽

Vol 461 (1) ◽

pp. 15-32 ◽

Cited By ~ 54

Author(s):

Eneda Toska ◽

Stefan G. E. Roberts

Keyword(s):

Target Genes ◽

Rna Binding ◽

Biological Effects ◽

Tumour Suppressor ◽

Complex Nature ◽

Wilms Tumour ◽

Post Translational Modifications ◽

Physiological Processes ◽

Binding Partners ◽

Multiple Binding

The WT1 (Wilms’ tumour 1) gene encodes a zinc finger transcription factor and RNA-binding protein that direct the development of several organs and tissues. WT1 manifests both tumour suppressor and oncogenic activities, but the reasons behind these opposing functions are still not clear. As a transcriptional regulator, WT1 can either activate or repress numerous target genes resulting in disparate biological effects such as growth, differentiation and apoptosis. The complex nature of WT1 is exemplified by a plethora of isoforms, post-translational modifications and multiple binding partners. How WT1 achieves specificity to regulate a large number of target genes involved in diverse physiological processes is the focus of the present review. We discuss the wealth of the growing molecular information that defines our current understanding of the versatility and utility of WT1 as a master regulator of organ development, a tumour suppressor and an oncogene.

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Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications

Frontiers in Oncology ◽

10.3389/fonc.2021.708765 ◽

2021 ◽

Vol 11 ◽

Author(s):

Khalid Otmani ◽

Philippe Lewalle

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Posttranscriptional Regulation ◽

Target Genes ◽

Critical Role ◽

Mature Mirnas ◽

Tumor Formation ◽

Clinical Implications ◽

Mirna Regulation ◽

Mirnas Expression

MicroRNAs (miRNAs) are noncoding RNAs that have been identified as important posttranscriptional regulators of gene expression. miRNAs production is controlled at multiple levels, including transcriptional and posttranscriptional regulation. Extensive profiling studies have shown that the regulation of mature miRNAs expression plays a causal role in cancer development and progression. miRNAs have been identified to act as tumor suppressors (TS) or as oncogenes based on their modulating effect on the expression of their target genes. Upregulation of oncogenic miRNAs blocks TS genes and leads to tumor formation. In contrast, downregulation of miRNAs with TS function increases the translation of oncogenes. Several miRNAs exhibiting TS properties have been studied. In this review we focus on recent studies on the role of TS miRNAs in cancer cells and the tumor microenvironment (TME). Furthermore, we discuss how TS miRNA impacts the aggressiveness of cancer cells, with focus of the mechanism that regulate its expression. The study of the mechanisms of miRNA regulation in cancer cells and the TME may paved the way to understand its critical role in the development and progression of cancer and is likely to have important clinical implications in a near future. Finally, the potential roles of miRNAs as specific biomarkers for the diagnosis and the prognosis of cancer and the replacement of tumor suppressive miRNAs using miRNA mimics could be promising approaches for cancer therapy.

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Interaction between androgen receptor and coregulator SLIRP is regulated by Ack1 tyrosine kinase and androgen

Scientific Reports ◽

10.1038/s41598-019-55057-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Dinuka De Silva ◽

Zhentao Zhang ◽

Yuanbo Liu ◽

Joel S. Parker ◽

Chenxi Xu ◽

...

Keyword(s):

Androgen Receptor ◽

Tyrosine Kinase ◽

Noncoding Rna ◽

Target Genes ◽

Rna Binding ◽

Nuclear Translocation ◽

Critical Role ◽

Dependent Manner ◽

Castration Resistant Prostate Cancer ◽

Stem Loop

AbstractAberrant activation of the androgen receptor (AR) may play a critical role in castration resistant prostate cancer. After ligand binding, AR is recruited to the androgen responsive element (ARE) sequences on the DNA where AR interaction with coactivators and corepressors modulates transcription. We demonstrated that phosphorylation of AR at Tyr-267 by Ack1/TNK2 tyrosine kinase results in nuclear translocation, DNA binding, and androgen-dependent gene transcription in a low androgen environment. In order to dissect downstream mechanisms, we searched for proteins whose interaction with AR was regulated by Ack1. SLIRP (SRA stem-loop interacting RNA binding protein) was identified as a candidate protein. Interaction between AR and SLIRP was disrupted by Ack1 kinase activity as well as androgen or heregulin treatment. The noncoding RNA, SRA, was required for AR-SLIRP interaction. SLIRP was bound to ARE’s of AR target genes in the absence of androgen. Treatment with androgen or heregulin led to dissociation of SLIRP from the ARE. Whole transcriptome analysis of SLIRP knockdown in androgen responsive LNCaP cells showed that SLIRP affects a significant subset of androgen-regulated genes. Our data suggest that Ack1 kinase and androgen regulate interaction between AR and SLIRP and that SLIRP functions as a coregulator of AR with properties of a corepressor in a context-dependent manner.

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Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism

Nuclear Receptor Signaling ◽

10.1621/nrs.07003 ◽

2009 ◽

Vol 7 (1) ◽

pp. nrs.07003 ◽

Cited By ~ 367

Author(s):

Anton M. Jetten

Keyword(s):

Circadian Clock ◽

Energy Homeostasis ◽

Potential Role ◽

Target Genes ◽

Critical Role ◽

Lymphoid Tissues ◽

Rhythmic Pattern ◽

Lineage Specification ◽

Orphan Receptors ◽

Physiological Processes

The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORα, -β, and -γ (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORa plays a critical role in the development of the cerebellum, that both RORα and RORβ are required for the maturation of photoreceptors in the retina, and that RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORγ in lineage specification of uncommitted CD4+T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.

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Divulging the Critical Role of HuR in Pancreatic Cancer as a Therapeutic Target and a Means to Overcome Chemoresistance

Cancers ◽

10.3390/cancers13184634 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4634

Author(s):

Dimitrios Goutas ◽

Nikolaos Goutas ◽

Stamatios Theocharis

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Target Genes ◽

Rna Binding ◽

Eating Habits ◽

Critical Role ◽

Chemotherapy Resistance ◽

Tumor Grade ◽

Lymph Node Status ◽

Therapeutic Modalities

Pancreatic cancer is set to become the most lethal and common type of cancer worldwide. This is partly attributed to the mutational burden that affects core signaling pathways and the crosstalk of tumor cells with their surrounding microenvironment, but it is also due to modern eating habits. Hyperadiposity along with the constant rise in metabolic syndrome’s incidence contribute to a state of metaflammation that impacts immune cells and causes them to shift towards an immunosuppressive phenotype that, ultimately, allows tumor cells to evade immune control. Unfortunately, among the conventional therapeutic modalities and the novel therapeutic agents introduced, pancreatic cancer still holds one of the lowest response rates to therapy. Human antigen R (HuR), an RNA binding protein (RBP), has been repeatedly found to be implicated in pancreatic carcinogenesis and chemotherapy resistance through the posttranscriptional binding and regulation of mRNA target genes. Additionally, its overexpression has been linked to adverse clinical outcomes, in terms of tumor grade, stage, lymph node status and metastasis. These properties suggest the prospective role that HuR’s therapeutic targeting can play in facilitating pancreatic neoplasia and could provide the means to overcome chemoresistance.

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RNA-binding proteins La and HuR cooperatively modulate translation repression of PDCD4 mRNA

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014894 ◽

2020 ◽

pp. jbc.RA120.014894

Author(s):

Ravi Kumar ◽

Dipak Kumar Poria ◽

Partho Sarothi Ray

Keyword(s):

Inflammatory Response ◽

Chronic Inflammation ◽

Rna Binding ◽

Rna Binding Proteins ◽

Critical Role ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Suppressor Gene ◽

Cooperative Action ◽

Translation Repression

Post-transcriptional regulation of gene expression plays a critical role in controlling the inflammatory response. An uncontrolled inflammatory response results in chronic inflammation, often leading to tumorigenesis. Programmed cell death 4 (PDCD4) is a pro-inflammatory tumor-suppressor gene which helps to prevent the transition from chronic inflammation to cancer. PDCD4 mRNA translation is regulated by an interplay between the oncogenic microRNA miR-21 and the RNA-binding protein (RBP) HuR in response to LPS stimulation, but the role of other regulatory factors remain unknown. Here we report that the RBP Lupus antigen (La) interacts with the 3’UTR of PDCD4 mRNA and prevents miR-21-mediated translation repression. While LPS causes nuclear-cytoplasmic translocation of HuR, it enhances cellular La expression. Remarkably, La and HuR were found to bind cooperatively to the PDCD4 mRNA and mitigate miR-21-mediated translation repression. The cooperative action of La and HuR reduced cell proliferation and enhanced apoptosis, reversing the pro-oncogenic function of miR-21. Together, these observations demonstrate a cooperative interplay between two RBPs, triggered differentially by the same stimulus, which exerts a synergistic effect on PDCD4 expression and thereby helps maintain a balance between inflammation and tumorigenesis.

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Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

Cellular Oncology ◽

10.1007/s13402-021-00626-9 ◽

2021 ◽

Author(s):

Chun Yang ◽

Stéphane Croteau ◽

Pierre Hardy

Keyword(s):

Histone Deacetylase ◽

Posttranslational Modifications ◽

Histone Deacetylases ◽

Muscle Development ◽

Target Genes ◽

Human Cancer ◽

Expression Patterns ◽

Aberrant Expression ◽

Physiological Processes ◽

Cancer Pathogenesis

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

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

Genes ◽

10.3390/genes12060883 ◽

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.

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PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22158298 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8298

Author(s):

Hugo Christian Monroy-Ramirez ◽

Marina Galicia-Moreno ◽

Ana Sandoval-Rodriguez ◽

Alejandra Meza-Rios ◽

Arturo Santos ◽

...

Keyword(s):

Liver Diseases ◽

Metabolic Regulation ◽

Structural Changes ◽

Critical Role ◽

The Body ◽

Molecular Characteristics ◽

Signal Pathways ◽

Virus Infections ◽

Physiological Processes ◽

Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

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Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

Biomedicines ◽

10.3390/biomedicines9070821 ◽

2021 ◽

Vol 9 (7) ◽

pp. 821

Author(s):

Wanglong Qiu ◽

Chia-Yu Kuo ◽

Yu Tian ◽

Gloria H. Su

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Critical Role ◽

Genetic Mutations ◽

Cancer Genetic ◽

Dual Roles ◽

Activin Signaling ◽

Physiological Processes ◽

Cancer Types ◽

Related Proteins

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

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