Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26

The TRIM-NHL protein Meiotic P26 (Mei-P26) acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes and spermatogenesis. Mei-P26 functions as a post-transcriptional regulator of gene expression, however, the molecular details of how its NHL domain selectively recognizes and regulates its mRNA targets have remained elusive. Here, we present the crystal structure of the Mei-P26 NHL domain at 1.6 Å resolution and identify key amino acids that confer substrate specificity and distinguish Mei-P26 from closely related TRIM-NHL proteins. Furthermore, we identify mRNA targets of Mei-P26 in cultured Drosophila cells and show that Mei-P26 can act as either a repressor or activator of gene expression on different RNA targets. Our work reveals the molecular basis of RNA recognition by Mei-P26 and the fundamental functional differences between otherwise very similar TRIM-NHL proteins.

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Translational control in the C. elegans hermaphrodite germ line

Genome ◽

10.1139/g09-090 ◽

2010 ◽

Vol 53 (2) ◽

pp. 83-102 ◽

Cited By ~ 9

Author(s):

Hilary Racher ◽

Dave Hansen

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Translational Control ◽

Translational Regulation ◽

Developmental Stages ◽

Germ Line ◽

Control Of Gene Expression ◽

Cell Fate Decisions ◽

C Elegans ◽

Mrna Targets

The formation of a fully developed gamete from an undifferentiated germ cell requires progression through numerous developmental stages and cell fate decisions. The precise timing and level of gene expression guides cells through these stages. Translational regulation is highly utilized in the germ line of many species, including Caenorhabditis elegans , to regulate gene expression and ensure the proper formation of gametes. In this review, we discuss some of the developmental stages and cell fate decisions involved in the formation of functional gametes in the C. elegans germ line in which translational control has been implicated. These stages include the mitosis versus meiosis decision, the sperm/oocyte decision, and gamete maturation. We also discuss some of the techniques used to identify mRNA targets; the identification of these targets is necessary to clearly understand the role each RNA-binding protein plays in these decisions. Relatively few mRNA targets have been identified, thus providing a major focus for future research. Finally, we propose some reasons why translational control may be utilized so heavily in the germ line. Given that many species have this substantial reliance on translational regulation for the control of gene expression in the germ line, an understanding of translational regulation in the C. elegans germ line is likely to increase our understanding of gamete formation in general.

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cis-Regulatory Remodeling of the SCL Locus during Vertebrate Evolution

Molecular and Cellular Biology ◽

10.1128/mcb.00870-10 ◽

2010 ◽

Vol 30 (24) ◽

pp. 5741-5751 ◽

Cited By ~ 13

Author(s):

Berthold Göttgens ◽

Rita Ferreira ◽

Maria-José Sanchez ◽

Shoko Ishibashi ◽

Juan Li ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulator ◽

Regulatory Elements ◽

Vertebrate Evolution ◽

Regulatory Mechanisms ◽

Regulatory Change ◽

Regulatory Modules ◽

Functional Differences ◽

Lower Vertebrates ◽

Transcription Factor Genes

ABSTRACT Development progresses through a sequence of cellular identities which are determined by the activities of networks of transcription factor genes. Alterations in cis-regulatory elements of these genes play a major role in evolutionary change, but little is known about the mechanisms responsible for maintaining conserved patterns of gene expression. We have studied the evolution of cis-regulatory mechanisms controlling the SCL gene, which encodes a key transcriptional regulator of blood, vasculature, and brain development and exhibits conserved function and pattern of expression throughout vertebrate evolution. SCL cis-regulatory elements are conserved between frog and chicken but accrued alterations at an accelerated rate between 310 and 200 million years ago, with subsequent fixation of a new cis-regulatory pattern at the beginning of the mammalian radiation. As a consequence, orthologous elements shared by mammals and lower vertebrates exhibit functional differences and binding site turnover between widely separated cis-regulatory modules. However, the net effect of these alterations is constancy of overall regulatory inputs and of expression pattern. Our data demonstrate remarkable cis-regulatory remodelling across the SCL locus and indicate that stable patterns of expression can mask extensive regulatory change. These insights illuminate our understanding of vertebrate evolution.

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The Drosophila RNA Helicase Belle (DDX3) Non-Autonomously Suppresses Germline Tumorigenesis Via Regulation of a Specific mRNA Set

Cells ◽

10.3390/cells9030550 ◽

2020 ◽

Vol 9 (3) ◽

pp. 550

Author(s):

Alexei A. Kotov ◽

Baira K. Godneeva ◽

Oxana M. Olenkina ◽

Vladimir E. Adashev ◽

Mikhail V. Trostnikov ◽

...

Keyword(s):

Germ Cells ◽

Ectopic Expression ◽

Germline Stem Cell ◽

Rna Helicases ◽

Developmental Defects ◽

Stem Cell Maintenance ◽

Mrna Targets ◽

Dead Box ◽

Cyst Cells ◽

Specific Mrna

DDX3 subfamily DEAD-box RNA helicases are essential developmental regulators of RNA metabolism in eukaryotes. belle, the single DDX3 ortholog in Drosophila, is required for fly viability, fertility, and germline stem cell maintenance. Belle is involved both in translational activation and repression of target mRNAs in different tissues; however, direct targets of Belle in the testes are essentially unknown. Here we showed that belle RNAi knockdown in testis cyst cells caused a disruption of adhesion between germ and cyst cells and generation of tumor-like clusters of stem-like germ cells. Ectopic expression of β-integrin in cyst cells rescued early stages of spermatogenesis in belle knockdown testes, indicating that integrin adhesion complexes are required for the interaction between somatic and germ cells in a cyst. To address Belle functions in spermatogenesis in detail we performed cross-linking immunoprecipitation and sequencing (CLIP-seq) analysis and identified multiple mRNAs that interacted with Belle in the testes. The set of Belle targets includes transcripts of proteins that are essential for preventing the tumor-like clusters of germ cells and for sustaining spermatogenesis. By our hypothesis, failures in the translation of a number of mRNA targets additively contribute to developmental defects observed in the testes with belle knockdowns both in cyst cells and in the germline.

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Distinct functional differences of human progesterone receptors A and B on gene expression and growth regulation in two endometrial carcinoma cell lines

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(02)00217-4 ◽

2003 ◽

Vol 10 (1) ◽

pp. 49-57 ◽

Cited By ~ 18

Author(s):

E Smid-Koopman

Keyword(s):

Gene Expression ◽

Endometrial Carcinoma ◽

Cell Lines ◽

Growth Regulation ◽

Carcinoma Cell ◽

Progesterone Receptors ◽

Endometrial Carcinoma Cell ◽

Carcinoma Cell Lines ◽

Functional Differences

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Faculty Opinions recommendation of Global changes in gene expression by human polymorphonuclear leukocytes during receptor-mediated phagocytosis: cell fate is regulated at the level of gene expression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005956.70707 ◽

2002 ◽

Author(s):

Steve Ward

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Polymorphonuclear Leukocytes ◽

Global Changes ◽

Human Polymorphonuclear Leukocytes

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FOXC1 in cancer development and therapy: deciphering its emerging and divergent roles

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834017742576 ◽

2017 ◽

Vol 9 (12) ◽

pp. 797-816 ◽

Cited By ~ 36

Author(s):

Zhi Yang ◽

Shuai Jiang ◽

Yicheng Cheng ◽

Tian Li ◽

Wei Hu ◽

...

Keyword(s):

Transcriptional Regulator ◽

Cancer Development ◽

Protein Activity ◽

Stem Cell Maintenance ◽

Cancer Migration ◽

Forkhead Box ◽

Pathological Conditions ◽

Clinical Biomarker ◽

Abnormal Cell Proliferation ◽

Cell Maintenance

Forkhead box C1 (FOXC1) is an essential member of the forkhead box transcription factors and has been highlighted as an important transcriptional regulator of crucial proteins associated with a wide variety of carcinomas. FOXC1 regulates tumor-associated genes and is regulated by multiple pathways that control its mRNA expression and protein activity. Aberrant FOXC1 expression is involved in diverse tumorigenic processes, such as abnormal cell proliferation, cancer stem cell maintenance, cancer migration, and angiogenesis. Herein, we review the correlation between the expression of FOXC1 and tumor behaviors. We also summarize the mechanisms of the regulation of FOXC1 expression and activity in physiological and pathological conditions. In particular, we focus on the pathological processes of cancer targeted by FOXC1 and discuss whether FOXC1 is good or detrimental during tumor progression. Moreover, FOXC1 is highlighted as a clinical biomarker for diagnosis or prognosis in various human cancers. The information reviewed here should assist in experimental designs and emphasize the potential of FOXC1 as a therapeutic target for cancer.

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Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Cancers ◽

10.3390/cancers13020350 ◽

2021 ◽

Vol 13 (2) ◽

pp. 350

Author(s):

Julianty Frost ◽

Mark Frost ◽

Michael Batie ◽

Hao Jiang ◽

Sonia Rocha

Keyword(s):

Gene Expression ◽

Hypoxia Inducible Factor ◽

Transcriptional Regulator ◽

Hydroxylase Activity ◽

Control Of Gene Expression ◽

Prolyl Hydroxylases ◽

Chromatin Organisation ◽

Sense And Respond ◽

Almost All ◽

And Function

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

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Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs

Cells ◽

10.3390/cells10030521 ◽

2021 ◽

Vol 10 (3) ◽

pp. 521

Author(s):

Catia Giovannini ◽

Francesca Fornari ◽

Fabio Piscaglia ◽

Laura Gramantieri

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Hepatitis Virus ◽

Notch Pathway ◽

Notch Receptor ◽

Gamma Secretase ◽

Stem Cell Maintenance ◽

Pathway Activation ◽

Promising Therapeutic Approach ◽

Conserved Genes

The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy.

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