scholarly journals Bystin in human cancer cells: intracellular localization and function in ribosome biogenesis

2007 ◽  
Vol 404 (3) ◽  
pp. 373-381 ◽  
Author(s):  
Masaya Miyoshi ◽  
Tetsuya Okajima ◽  
Tsukasa Matsuda ◽  
Michiko N. Fukuda ◽  
Daita Nadano
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Ribosomal Rna ◽  
Mammalian Cells ◽  
Ribosome Biogenesis ◽  
Human Cancer ◽  
Intracellular Localization ◽  
Promote Cell Proliferation ◽  
Human Cancer Cell Lines ◽  
Nucleolar Stress

Although bystin has been identified as a protein potentially involved in embryo implantation (a process unique to mammals) in humans, the bystin gene is evolutionarily conserved from yeast to humans. DNA microarray data indicates that bystin is overexpressed in human cancers, suggesting that it promotes cell growth. We undertook RT (reverse transcription)–PCR and immunoblotting, and confirmed that bystin mRNA and protein respectively are expressed in human cancer cell lines, including HeLa. Subcellular fractionation identified bystin protein as nuclear and cytoplasmic, and immunofluorescence showed that nuclear bystin localizes mainly in the nucleolus. Sucrose gradient ultracentrifugation of total cytoplasmic ribosomes revealed preferential association of bystin with the 40S subunit fractions. To analyse its function, bystin expression in cells was suppressed by RNAi (RNA interference). Pulse–chase analysis of ribosomal RNA processing suggested that bystin knockdown delays processing of 18S ribosomal RNA, a component of the 40S subunit. Furthermore, this knockdown significantly inhibited cell proliferation. Our findings suggest that bystin may promote cell proliferation by facilitating ribosome biogenesis, specifically in the production of the 40S subunit. Localization of bystin to the nucleolus, the site of ribosome biogenesis, was blocked by low concentrations of actinomycin D, a reagent that causes nucleolar stress. When bystin was transiently overexpressed in HeLa cells subjected to nucleolar stress, nuclear bystin was included in particles different from the nuclear stress granules induced by heat shock. In contrast, cytoplasmic bystin was barely affected by nucleolar stress. These results suggest that, while bystin may play multiple roles in mammalian cells, a conserved function is to facilitate ribosome biogenesis required for cell growth.

scholarly journals Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 503 ◽  
Author(s):  
Sabrina Adorisio ◽  
Alessandra Fierabracci ◽  
Isabella Muscari ◽  
Anna Liberati ◽  
Lorenza Cannarile ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Fas Ligand ◽  
Human Cancer ◽  
Dependent Manner ◽  
Food Contaminants ◽  
Human Cancer Cell Lines ◽  
Hematological Cancers ◽  
The Impact

Cladosporium species are endophytic fungi that grow on organic matter and are considered food contaminants. The anti-microbial and anti-tumor naphthoquinones fusarubin (FUS) and anhydrofusarubin (AFU) were isolated using column chromatography from a Cladosporium species residing inside Rauwolfia leaves. The impact of FUS and AFU on cell growth was assessed in acute myeloid leukemia (OCI-AML3) and other hematologic tumor cell lines (HL-60, U937, and Jurkat). Treatment with FUS or AFU reduced the number of OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses showed that this effect was accompanied by diverse impairments in cell cycle progression. Specifically, FUS (20 or 10 μg/mL significantly decreased the percentage of cells in S phase and increased the percentage of cells in G2/M phase, whereas AFU increased the percentage of cells in G0/G1 phase (50 and 25 μg/mL) and decreased the percentage of cells in S (50 μg/mL) and G2/M (50 and 25 μg/mL) phases. Both substances significantly increased apoptosis at higher concentrations. The effects of FUS were more potent than those of AFU, with FUS up-regulating p21 expression in a p53-dependent manner, as detected by Western blot analyses, likely the consequence of decreased ERK phosphorylation and increased p38 expression (both of which increase p21 stability). FUS also decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers.

scholarly journals Actions and Potential Therapeutic Applications of Growth Hormone–Releasing Hormone Agonists

Endocrinology ◽  
2019 ◽  
Vol 160 (7) ◽  
pp. 1600-1612 ◽  
Author(s):  
Andrew V Schally ◽  
Xianyang Zhang ◽  
Renzhi Cai ◽  
Joshua M Hare ◽  
Riccarda Granata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cardiac Tissue ◽  
Human Cancer ◽  
Large Body ◽  
Neuroprotective Effects ◽  
Promote Cell Proliferation ◽  
Therapeutic Applications ◽  
Human Cancer Cells

Abstract In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use.

scholarly journals LncRNA GATA6-AS inhibits cancer cell proliferation and promotes cancer cell apoptosis in cervical cancer by down-regulating miR-205

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaoying Zhao ◽  
Huzhong Zheng ◽  
Jun Chen
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Human Cancer ◽  
Over Expression ◽  
Endothelial Cell Growth ◽  
Healthy Females

Abstract Background Dysregulated endothelial cell growth is involved in many types of human cancer, including cervical cancer. LncRNA GATA6-AS was reported to regulate endothelial cell growth, suggesting it might involve in cervical cancer. Our study was carried out to explore the involvement of GATA6-AS in cervical squamous cell carcinoma (CSCC), a subtype of cervical cancer. Methods To explore the expression of GATA6-AS, RT-qPCR was performed to detect GATA6-AS in plasma of 65 CSCC patients and 58 healthy females. To detect the expression of GATA6-AS, total RNAs were extracted. Results We found that plasma GATA6-AS expression was down-regulated in CSCC patients than that in healthy females, and HPV infection did not significantly affect the plasma expression of GATA6-AS. Moreover, we found that plasma GATA6-AS showed diagnostic values for CSCC by performing ROC curve analysis. The expression of miR-205 in plasma was also found to be up-regulated in CSCC patients than that in healthy females and inversely correlated with the expression of GATA6-AS in CSCC patients. Furthermore, over-expression of miR-205 did not significantly affect the expression of GATA6-AS in CSCC cells, while over-expression of GATA6-AS down-regulated miR-205 expression. In addition, GATA6-AS over-expression inhibited CSCC cell proliferation and promoted CSCC cell apoptosis, while miR-205 over-expression played opposite roles and attenuated the effects of GATA6-AS over-expression on CSCC cells. Conclusion Taken together, these results suggest that GATA6-AS may inhibit cell proliferation and promote cell apoptosis in CSCC by down-regulating miR-205.

scholarly journals Polysome arrest restricts miRNA turnover by preventing exosomal export of miRNA in growth-retarded mammalian cells

2015 ◽  
Vol 26 (6) ◽  
pp. 1072-1083 ◽  
Author(s):  
Souvik Ghosh ◽  
Mainak Bose ◽  
Anirban Ray ◽  
Suvendra N. Bhattacharyya
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Subcellular Distribution ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Mature Mirnas ◽  
Regulatory Rnas ◽  
The Stability ◽  
External Stimuli

MicroRNAs (miRNAs) are tiny posttranscriptional regulators of gene expression in metazoan cells, where activity and abundance of miRNAs are tightly controlled. Regulated turnover of these regulatory RNAs is important to optimize cellular response to external stimuli. We report that the stability of mature miRNAs increases inversely with cell proliferation, and the increased number of microribonucleoproteins (miRNPs) in growth-restricted mammalian cells are in turn associated with polysomes. This heightened association of miRNA with polysomes also elicits reduced degradation of target mRNAs and impaired extracellular export of miRNA via exosomes. Overall polysome sequestration contributes to an increase of cellular miRNA levels but without an increase in miRNA activity. Therefore miRNA activity and turnover can be controlled by subcellular distribution of miRNPs that may get differentially regulated as a function of cell growth in mammalian cells.

scholarly journals Matrix metalloproteinase-2 mediates ribosomal RNA transcription by cleaving nucleolar histones

2020 ◽  
Author(s):  
Mohammad A.M. Ali ◽  
Javier A. Garcia-Vilas ◽  
Christopher R. Cromwell ◽  
Basil P. Hubbard ◽  
Michael J. Hendzel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Matrix Metalloproteinase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Histone H3 ◽  
Epigenetic Mechanism ◽  
Matrix Metalloproteinase 2 ◽  
Rrna Gene ◽  
Rrna Transcription ◽  
Genes Encoding

AbstractCell proliferation and survival require continuous ribosome biogenesis and protein synthesis. Genes encoding ribosomal RNA (rRNA) are physically located in a specialized substructure within the nucleus known as the nucleolus, which has a central role in the biogenesis of ribosomes. Matrix metalloproteinase-2 (MMP-2) was previously detected in the nucleus. However, its role there is elusive. Herein we report that MMP-2 resides within the nucleolus to regulate rRNA transcription. MMP-2 is enriched at the promoter region of rRNA gene repeats and its inhibition downregulates pre-rRNA transcription. The N-terminal tail of histone H3 is clipped by MMP-2 in the nucleolus and is associated with increased rRNA transcription. Knocking down/out MMP-2 or inhibiting its activity prevents histone H3 cleavage and reduces both rRNA transcription and cell proliferation. In addition to the known extracellular roles of MMP-2 in tumor growth, our data reveal an epigenetic mechanism whereby intranucleolar MMP-2 regulates cell proliferation through histone proteolysis and facilitation of rRNA transcription.

scholarly journals A Drosophila RNA helicase gene, pitchoune, is required for cell growth and proliferation and is a potential target of d-Myc

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3571-3584 ◽  
Author(s):  
S. Zaffran ◽  
A. Chartier ◽  
P. Gallant ◽  
M. Astier ◽  
N. Arquier ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Protein Biosynthesis ◽  
Ectopic Expression ◽  
Rna Helicase ◽  
Potential Target ◽  
Dead Box ◽  
First Instar ◽  
Cell Growth And Proliferation

This article describes the characterization of a new Drosophila gene that we have called pitchoune (pit) (meaning small in Provence) because mutations in this gene produce larvae that cannot grow beyond the first instar larval stage although they can live as long as 7–10 days. All the tissues are equally affected and the perfectly shaped larvae are indistinguishable from first instar wild-type animals. Analysis of mutant somatic clones suggests a function in cell growth and proliferation, which is supported by the fact that cell proliferation is promoted by pit overexpression. Tagged-Pit, when transfected in S2 cells, localizes mainly to the nucleolus, pointing towards a possible role in ribosome biogenesis and, consequently, in protein biosynthesis. pit encodes a DEAD-box RNA helicase, a family of proteins involved in the control of RNA structure in many cellular processes and its closest homologue is a human DEAD-box RNA helicase, MrDb, whose corresponding gene transcription is directly activated by Myc-Max heterodimers (Grandori, C., Mac, J., Siebelt, F., Ayer, D. E. and Eisenman, R. N. (1996) EMBO J. 15, 4344–4357). The patterns of expression of d-myc and pit are superimposable. Ectopic expression of myc in the nervous system drives an ectopic expression of pit in this tissue indicating that in Drosophila as well, pit is a potential target of d-Myc. These results suggest that myc might promote cell proliferation by activating genes that are required in protein biosynthesis, thus linking cell growth and cell proliferation.

scholarly journals Myc-dependent cell competition and proliferative response requires induction of the ribosome biogenesis regulator Peter Pan

2020 ◽  
Author(s):  
Norman Zielke ◽  
Anna Vähärautio ◽  
Jianping Liu ◽  
Jussi Taipale
Keyword(s):  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Target Genes ◽  
Human Cancer ◽  
Large Set ◽  
Cell Competition ◽  
Peter Pan ◽  
Promoter Regions ◽  
E Box ◽  
Induced Apoptosis

AbstractThe transcription factor Myc is activated in most major forms of human cancer. Myc regulates a large set of target genes, and drives cell growth across animal phyla. However, it has not been clear which target genes are required for Myc-induced growth, and whether the targets are individually necessary or act in an additive fashion. Here, we have used comparative functional genomics to identify a core set of Myc target genes whose regulation is conserved between humans and Drosophila melanogaster. Most of these targets are essential genes involved in ribosome biogenesis and ribonucleotide metabolism. To identify Drosophila genes whose upregulation is necessary for Myc induced growth, we deleted the Myc binding sites (E-boxes) in the promoter regions of four genes using CRISPR/Cas9. All mutant flies were homozygous viable, indicating that E-box sequences are not required for basal expression of the Myc target genes. E-Box deletions in RpS20, RpS24 and Nop56 did not cause strong growth phenotypes. However, deletion of the E-box in the rRNA processing factor Peter Pan (ppan) made the flies resistant to Myc-induced cell growth, without affecting Myc-induced apoptosis. Despite their failure to respond to Myc, the ppanEbox−/− flies are healthy and display only a minor developmental delay, suggesting that it may be possible to treat or prevent tumorigenesis by targeting individual downstream targets of Myc.

scholarly journals Las1L Is a Nucleolar Protein Required for Cell Proliferation and Ribosome Biogenesis

2010 ◽  
Vol 30 (18) ◽  
pp. 4404-4414 ◽  
Author(s):  
Christopher D. Castle ◽  
Erica K. Cassimere ◽  
Jinho Lee ◽  
Catherine Denicourt
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Nucleolar Protein ◽  
28S Rrna ◽  
Rrna Processing ◽  
Tumor Suppressor P53 ◽  
Growth Increase ◽  
Multistep Process

ABSTRACT Ribosome biogenesis is a highly regulated process ensuring that cell growth (increase in biomass) is coordinated with cell proliferation. The formation of eukaryotic ribosomes is a multistep process initiated by the transcription and processing of rRNA in the nucleolus. Concomitant with this, several preribosomal particles, which transiently associate with numerous nonribosomal factors before mature 60S and 40S subunits are formed and exported in the cytoplasm, are generated. Here we identify Las1L as a previously uncharacterized nucleolar protein required for ribosome biogenesis. Depletion of Las1L causes inhibition of cell proliferation characterized by a G1 arrest dependent on the tumor suppressor p53. Moreover, we demonstrate that Las1L is crucial for ribosome biogenesis and that depletion of Las1L leads to inhibition of rRNA processing and failure to synthesize the mature 28S rRNA. Taken together, our data demonstrate that Las1L is essential for cell proliferation and biogenesis of the 60S ribosomal subunit.

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