scholarly journals Telomerase as a therapeutic target.

1996 ◽  
Vol 43 (3) ◽  
pp. 531-538 ◽  
Author(s):  
L Huminiecki
Keyword(s):  
Bone Marrow ◽  
Therapeutic Target ◽  
Cancer Biology ◽  
Critical Length ◽  
Telomerase Activity ◽  
Telomeric Dna ◽  
Telomerase Inhibition ◽  
Normal Human ◽  
Peripheral Leukocytes ◽  
Biology Research

Ribonucleoprotein telomerase is an enzyme that elongates telomeric DNA. In cells without detectable telomerase activity telomeres shorten with every cell generation and reaching critical length is a signal for cell death. Normal human somatic cells express undetectable, or low (bone marrow and peripheral leukocytes), telomerase activity. Reactivation of telomerase (immortalization) is probably necessary during development of a fully malignant cancer. Consequently, telomerase was proposed to be a therapeutic target for the cancer therapy. Potential results (including side-effects) of telomerase inhibition are being considered. After all, telomerase inhibition can be useful not only in the therapy, but also in cancer biology research, elucidating ageing and immortalization phenomena.

scholarly journals Human Telomerase and Its Regulation

2002 ◽  
Vol 66 (3) ◽  
pp. 407-425 ◽  
Author(s):  
Yu-Sheng Cong ◽  
Woodring E. Wright ◽  
Jerry W. Shay
Keyword(s):  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Telomerase Activity ◽  
Cellular Aging ◽  
Telomeric Dna ◽  
Associated Proteins ◽  
Functional Complex ◽  
Length Regulation ◽  
Normal Human ◽  
Human Telomerase

SUMMARY The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

scholarly journals Quantitative Biology of Human Shelterin and Telomerase: Searching for the Weakest Point

2019 ◽  
Vol 20 (13) ◽  
pp. 3186 ◽  
Author(s):  
Veverka ◽  
Janovič ◽  
Hofr
Keyword(s):  
Structural Information ◽  
Anticancer Therapy ◽  
Telomerase Activity ◽  
Future Research ◽  
Quantitative Biology ◽  
Telomeric Dna ◽  
Telomerase Inhibition ◽  
Promising Target ◽  
The Status ◽  
Associated Proteins

The repetitive telomeric DNA at chromosome ends is protected from unwanted repair by telomere-associated proteins, which form the shelterin complex in mammals. Recent works have provided new insights into the mechanisms of how human shelterin assembles and recruits telomerase to telomeres. Inhibition of telomerase activity and telomerase recruitment to chromosome ends is a promising target for anticancer therapy. Here, we summarize results of quantitative assessments and newly emerged structural information along with the status of the most promising approaches to telomerase inhibition in cancer cells. We focus on the mechanism of shelterin assembly and the mechanisms of how shelterin affects telomerase recruitment to telomeres, addressing the conceptual dilemma of how shelterin allows telomerase action and regulates other essential processes. We evaluate how the identified critical interactions of telomerase and shelterin might be elucidated in future research of new anticancer strategies.

scholarly journals Telomerase activity in normal leukocytes and in hematologic malignancies

Blood ◽  
1995 ◽  
Vol 85 (9) ◽  
pp. 2315-2320 ◽  
Author(s):  
CM Counter ◽  
J Gupta ◽  
CB Harley ◽  
B Leber ◽  
S Bacchetti
Keyword(s):  
Bone Marrow ◽  
Hematologic Malignancies ◽  
Telomerase Activity ◽  
Carcinoma Cells ◽  
Lymphocytic Leukemia ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Somatic Tissues ◽  
Low Levels

Telomeres are essential for function and stability of eukaryotic chromosomes. In the absence of telomerase, the enzyme that synthesizes telomeric DNA, telomeres shorten with cell division, a process thought to contribute to cell senescence and the proliferative crisis of transformed cells. We reported telomere stabilization concomitant with detection of telomerase activity in cells immortalized in vitro and in ovarian carcinoma cells, and suggested that telomerase is essential for unlimited cell proliferation. We have now examined the temporal pattern of telomerase expression in selected hematologic malignancies. We found that, unlike other somatic tissues, peripheral, cord blood, and bone marrow leukocytes from normal donors expressed low levels of telomerase activity. In leukocytes from chronic lymphocytic leukemia (CLL) patients, activity was lower than in controls in early disease, and comparable with controls in late disease. Relative to bone marrow, telomerase activity was enhanced in myelodysplastic syndrome (MDS) and more significantly so in acute myeloid leukemia (AML). Regardless of telomerase levels, telomeres shortened with progression of the diseases. Our results suggest that early CLL and MDS cells lack an efficient mechanism of telomere maintenance and that telomerase is activated late in the progression of these cancers, presumably when critical telomere loss generates selective pressure for cell immortality.

FRACTIONATION OF NORMAL HUMAN BONE MARROW ON ALBUMIN GRADIENTS

1974 ◽  
Vol 52 (5) ◽  
pp. 767-778 ◽  
Author(s):  
KA Rickard ◽  
L Dunleavy ◽  
R Brown ◽  
H Kronenberg
Keyword(s):  
Bone Marrow ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Normal Human ◽  
Normal Human Bone Marrow

The effect of vanocomycin and teicoplanin on normal human bone marrow progenitor cells

1992 ◽  
Vol 30 (4) ◽  
pp. 559-560
Author(s):  
R. DE BOCK ◽  
D. VAN BOCKSTAELE ◽  
H. SNOECK ◽  
F. LARDON ◽  
M. PEETERMANS
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Bone Marrow Progenitor Cells ◽  
Bone Marrow Progenitor ◽  
Normal Human ◽  
Normal Human Bone Marrow

Abstract T P238: Microglial CX3CR1 Required for M2 Polarization and Recovery After Intracerebral Hemorrhage

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Roslyn A Taylor ◽  
Matthew D Hammond ◽  
Youxi Ai ◽  
Lauren H Sansing
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Intracerebral Hemorrhage ◽  
Gait Analysis ◽  
Functional Outcome ◽  
Cylinder Test ◽  
M2 Microglia ◽  
Inflammatory Phenotype ◽  
Peripheral Leukocytes ◽  
The Right

Introduction: Intracerebral hemorrhage (ICH) results in the activation of microglia, the resident immune cells of the central nervous system. Microglia may polarize into an M1, pro-inflammatory phenotype, or an M2 phenotype associated with repair. CX3CR1 is a chemokine receptor on microglia and monocyte subsets. CX3CR1-null microglia have been shown to have dysregulated inflammation. We hypothesize that CX3CR1-null microglia have a prolonged M1 phenotype, contributing to worse functional outcome after ICH. Methods: ICH was modeled by injection of 20μl of blood into the right striatum. Neurological deficit was quantified using digital gait analysis, cylinder test, and beam walking. Mice were sacrificed 14 days after ICH; brains were harvested for flow cytometry and immunohistochemistry (IHC). C57BL/6 (WT) and CX3CR1 GFP/GFP (CX3CR1-null) mice were irradiated and reconstituted with bone marrow from WT mice carrying the congenic marker CD45.1 to generate bone marrow chimeras (CD45.1WT or CD45.1CX3CR1-null). M1 microglia were identified as expressing MHCII and M2 microglia with CD206. Results: The CD45.1CX3CR1-null mice show worse functional outcome 14 days after ICH by cylinder test (p=0.002), beam walking (p=<0.001) and gait analysis (p=0.02). By flow cytometry, few peripheral leukocytes remain in the brain at 14 days, indicating that F4/80 + and CD11b + cells visualized by IHC are likely microglia, not peripheral macrophages. By IHC, CD45.1 CX3CR1-null mice have significantly more amoeboid F4/80 + MHCII + cells per field (M1 microglia) than CD45.1WT mice (p=0.02). CD45.1 CX3CR1-null mice have significantly fewer CD11b + CD206 + cells per field (M2 microglia) compared to CD45.1WT mice (p=0.04). Conclusions: Our results suggest microglial CX3CR1 signaling is necessary for microglia to transition from M1 to M2 and contribute to recovery after ICH.

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