scholarly journals Telomerase activation in mouse mammary tumors: lack of detectable telomere shortening and evidence for regulation of telomerase RNA with cell proliferation.

1996 ◽  
Vol 16 (7) ◽  
pp. 3765-3772 ◽  
Author(s):  
D Broccoli ◽  
L A Godley ◽  
L A Donehower ◽  
H E Varmus ◽  
T de Lange
Keyword(s):  
Cell Proliferation ◽  
Tumor Development ◽  
Mammary Tumorigenesis ◽  
Mammary Tumors ◽  
Mammary Glands ◽  
Telomerase Activity ◽  
Telomerase Rna ◽  
Proliferating Cells ◽  
Telomere Shortening ◽  
Mouse Mammary Tumors

Activation of telomerase in human cancers is thought to be necessary to overcome the progressive loss of telomeric DNA that accompanies proliferation of normal somatic cells. According to this model, telomerase provides a growth advantage to cells in which extensive terminal sequence loss threatens viability. To test these ideas, we have examined telomere dynamics and telomerase activation during mammary tumorigenesis in mice carrying a mouse mammary tumor virus long terminal repeat-driven Wnt-1 transgene. We also analyzed Wnt-1-induced mammary tumors in mice lacking p53 function. Normal mammary glands, hyperplastic mammary glands, and mammary carcinomas all had the long telomeres (20 to 50 kb) typical of Mus musculus and did not show telomere shortening during tumor development. Nevertheless, telomerase activity and the RNA component of the enzyme were consistently upregulated in Wnt-1-induced mammary tumors compared with normal and hyperplastic tissues. The upregulation of telomerase activity and RNA also occurred during tumorigenesis in p53-deficient mice. The expression of telomerase RNA correlated strongly with histone H4 mRNA in all normal tissues and tumors, indicating that the RNA component of telomerase is regulated with cell proliferation. Telomerase activity in the tumors was elevated to a greater extent than telomerase RNA, implying that the enzymatic activity of telomerase is regulated at additional levels. Our data suggest that the mechanism of telomerase activation in mouse mammary tumors is not linked to global loss of telomere function but involves multiple regulatory events including upregulation of telomerase RNA in proliferating cells.

scholarly journals Suppression of cell proliferation and telomerase activity in 4-(hydroxyphenyl)retinamide-treated mammary tumors

1999 ◽  
Vol 20 (5) ◽  
pp. 879-883 ◽  
Author(s):  
Andrezj Bednarek ◽  
Anne Shilkaitis ◽  
Albert Green ◽  
Ronald Lubet ◽  
Gary Kelloff ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mammary Tumors ◽  
Telomerase Activity

scholarly journals Targeted 2′-O Methylation at a Nucleotide within the Pseudoknot of Telomerase RNA Reduces Telomerase Activity In Vivo

2010 ◽  
Vol 30 (18) ◽  
pp. 4368-4378 ◽  
Author(s):  
Chao Huang ◽  
Yi-Tao Yu
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Triple Helix ◽  
Telomerase Activity ◽  
Rna Modification ◽  
Telomerase Rna ◽  
Telomere Shortening ◽  
Pseudoknot Structure ◽  
Novel Approach ◽  
Telomere Lengthening

ABSTRACT Telomerase RNA is an essential component of telomerase, a ribonucleoprotein enzyme that maintains chromosome ends in most eukaryotes. Here we employ a novel approach, namely, RNA-guided RNA modification, to assess whether introducing 2′-O methylation into telomerase RNA can influence telomerase activity in vivo. We generate specific 2′-O methylation sites in and adjacent to the triple helix (within the conserved pseudoknot structure) of Saccharomyces cerevisiae telomerase RNA (TLC1). We show that 2′-O methylation at U809 reduces telomerase activity, resulting in telomere shortening, whereas 2′-O methylation at A804 or A805 leads to moderate telomere lengthening. Importantly, we also show that targeted 2′-O methylation does not affect TLC1 levels and that 2′-O-methylated TLC1 appears to be efficiently assembled into telomerase ribonucleoprotein. Our results demonstrate that RNA-guided RNA modification is a highly useful approach for modulating telomerase activity.

scholarly journals Development and Validation of an Image Analysis System for the Measurement of Cell Proliferation in Mammary Glands of Rats

2019 ◽  
Vol 47 (5) ◽  
pp. 634-644 ◽  
Author(s):  
Klaus Lindauer ◽  
Thomas Bartels ◽  
Petra Scherer ◽  
Mostafa Kabiri
Keyword(s):  
Cell Proliferation ◽  
Image Analysis ◽  
Mammary Glands ◽  
Absolute Difference ◽  
Image Analysis System ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Validation Data ◽  
Manual Counting ◽  
Analysis System

Reliable detection and measurement of cell proliferation are essential in the preclinical assessment of carcinogenic risk of therapeutics. In this context, the assessment of mitogenic potential on mammary glands is crucial in the preclinical safety evaluation of novel insulins. The existing manual counting is time-consuming and subject to operator bias. To standardize the processes, make it faster, and resistant to errors, we developed a semiautomated image analysis system (CEPA software, which is open-source) for counting of proliferating cells in photomicrographs of mammary gland sections of rats labeled with Ki-67. We validated the software and met the predefined targets for specificity, accuracy, and reproducibility. In comparison to manual counting, the respective mean differences in absolute labeling indices (LIs) for CEPA software were 3.12% for user 1 and 3.05% for user 2. The respective regression analysis revealed a good correlation between the CEPA software user and manual counting. Moreover, the CEPA software showed enhanced reproducibility between independent users. The interuser variability is centered around 0 and the absolute difference was about 0.53% LI. Based on validation data, our software has superiority to the manual counting and is a valid and reliable tool for the routine analysis of cell proliferation in mammary glands from rats exposed to insulin analogs.

scholarly journals Human Telomerase RNA Protein Encoded by Telomerase RNA is Involved in Metabolic Responses

2021 ◽  
Vol 9 ◽  
Author(s):  
Viktoriia Shliapina ◽  
Mariia Koriagina ◽  
Daria Vasilkova ◽  
Vadim Govorun ◽  
Olga Dontsova ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Immune Cell ◽  
Protein Biosynthesis ◽  
Stem Cell Differentiation ◽  
Telomerase Activity ◽  
Telomerase Rna ◽  
Ampk Signaling ◽  
Human Telomerase

Cell proliferation is associated with increased energy and nutrients consumption. Metabolism switch from oxidative phosphorylation to glycolysis and telomerase activity are induced during stimulation of proliferation, such as tumorigenesis, immune cell activation, and stem cell differentiation, among others. Telomerase RNA is one of the core components of the telomerase complex and participates in survival mechanisms that are activated under stress conditions. Human telomerase RNA protein (hTERP) is encoded by telomerase RNA and has been recently shown to be involved in autophagy regulation. In this study, we demonstrated the role of hTERP in the modulation of signaling pathways regulating autophagy, protein biosynthesis, and cell proliferation. The AMPK signaling pathway was affected in cells deficient of hTERP and when hTERP was overexpressed. The appearance of hTERP is important for metabolism switching associated with the accelerated proliferation of cells in healthy and pathological processes. These findings demonstrate the connection between telomerase RNA biogenesis and function and signaling pathways.

scholarly journals The 5′ Arm of Kluyveromyces lactis Telomerase RNA Is Critical for Telomerase Function

2008 ◽  
Vol 28 (6) ◽  
pp. 1875-1882 ◽  
Author(s):  
Majdi M. Kabaha ◽  
Benny Zhitomirsky ◽  
Irit Schwartz ◽  
Yehuda Tzfati
Keyword(s):  
Yeast Species ◽  
Kluyveromyces Lactis ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Null Mutation ◽  
Telomerase Rna ◽  
Catalytic Core ◽  
Telomere Shortening ◽  
Eukaryotic Chromosome ◽  
Recombination Pathway

ABSTRACT Telomerase is a ribonucleoprotein reverse transcriptase that copies a short template within its integral telomerase RNA moiety (TER) onto eukaryotic chromosome ends, thus compensating for incomplete replication and degradation. The highly divergent yeast TER is structured in three long arms, with a catalytic core at its center. A binding site for the protein Ku80 is conserved within the 5′ arm of TER in Saccharomyces but not in Kluyveromyces budding yeast species. Consistently, KU80 deletion in Kluyveromyces lactis does not affect telomere length, while it causes telomere shortening in Saccharomyces cerevisiae. We found elements in the 5′ arm of K. lactis TER that are crucial for telomerase activity and stability. However, we found no indication of the association of Ku80 with this arm. Although the overexpression of Ku80 rescues a particular mutation in K. lactis TER1 that phenocopies a telomerase null mutation, this effect is indirect, caused by the repression of the recombination pathway competing for telomere maintenance. Interestingly, the overexpression of Est3, an essential telomerase protein whose function is still unknown, suppresses the phenotypes of mutations in this arm. These results indicate that the 5′ arm of K. lactis TER has critical roles in telomerase function, which may be linked to the function of Est3.

Great Increase of Numbers of Virus Particles by Irradiating C3H Mouse Mammary Tumors Transplanted into Male Mice

1972 ◽  
Vol 30 ◽  
pp. 272-273
Author(s):  
P. J. Melnick ◽  
J. W. Cha ◽  
E. Samouhos
Keyword(s):  
Subcutaneous Tissue ◽  
Mammary Tumors ◽  
The Body ◽  
X Ray ◽  
Virus Particles ◽  
Mouse Mammary Tumors ◽  
Transplantable Tumors ◽  
C3h Mice ◽  
Cobalt Radiation ◽  
Enzyme Changes

Spontaneous mammary tumors in females of a high tumor strain of C3H mice were cut into small fragments that were Implanted into the subcutaneous tissue of the back of males of the same strain, where they grew as transplantable tumors. When about Cm. In diameter daily fractional radiation was begun, applied to the tumors, the rest of the body being shielded by a lead shield. Two groups were treated with 150 and 200 r X-ray dally, of half value layer 0.6mm. copper; a third group was treated with 500 r cobalt radiation dally. The primary purpose was to examine the enzyme changes during radiation, with histochemlcal technics.

scholarly journals Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan M. Baxley ◽  
Wendy Leung ◽  
Megan M. Schmit ◽  
Jacob Peter Matson ◽  
Lulu Yin ◽  
...  
Keyword(s):  
Immune Cell ◽  
Nk Cell ◽  
Restrictive Cardiomyopathy ◽  
Telomerase Activity ◽  
Compound Heterozygous ◽  
Minichromosome Maintenance ◽  
Telomere Shortening ◽  
Clinical Phenotypes ◽  
Eukaryotic Dna ◽  
Minichromosome Maintenance Protein

AbstractMinichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

scholarly journals Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas

Oncogene ◽  
2004 ◽  
Vol 23 (36) ◽  
pp. 6047-6055 ◽  
Author(s):  
Vassiliki Theodorou ◽  
Mandy Boer ◽  
Britta Weigelt ◽  
Jos Jonkers ◽  
Martin van der Valk ◽  
...  
Keyword(s):  
Insertional Mutagenesis ◽  
Mammary Tumors ◽  
Breast Carcinomas ◽  
Human Breast ◽  
Human Breast Carcinomas ◽  
Mouse Mammary Tumors

Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development

2021 ◽  
Author(s):  
Fatma El Zahraa Mohamed ◽  
Rajiv Jalan ◽  
Shane Minogue ◽  
Fausto Andreola ◽  
Abeba Habtesion ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Development ◽  
Cholangiocarcinoma Cell
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