Human Telomerase and Its Regulation

Cong, Yu Sheng; Wright, Woodring E.

doi:10.1128/mmbr.66.3.407-425.2002

Cited by 761 publications

(705 citation statements)

References 258 publications

(388 reference statements)

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“…The core of this enzyme from all species is minimally composed of a protein-catalytic subunit and a single-stranded RNA called TERT and TR, respectively (Nugent and Lundblad, 1998;Collins, 2006). The expression of TERT has been demonstrated as a rate-limiting step in human cellular telomerase activation, and it is suppressed by multiple tumor-suppressor pathways in normal human cells but is activated by numerous oncogenic transcription factors (Meyerson et al, 1997;Liu et al, 2000;Cong et al, 2002;Lin and Elledge, 2003;Goueli and Janknecht, 2004). After its expression, regulations of the subcellular transportation of the TERT protein contribute to telomere homeostasis maintenance in telomerase-positive cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Zhang

Dong

H.³

et al. 2011

Oncogene

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Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the downregulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies.

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Section: Introductionmentioning

confidence: 99%

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Zhang

Dong

H.³

et al. 2011

Oncogene

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“…The activity of the ribonucleoprotein complex telomerase is reliant on the expression of both hTR and hTERT genes, the regulation of which is tightly coordinated on multiple levels by transcriptional, post-transcriptional (Zhao et al, 2000(Zhao et al, , 2005Cong et al, 2002;Anderson et al, 2006;Bilsland et al, 2006) and epigenetic mechanisms (Atkinson et al, 2005;Serakinci et al, 2006). In most normal somatic cells, telomerase is inactivated following development so that telomeres shorten after each round of replication until they reach a critical length, signalling senescence or cell death.…”

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confidence: 99%

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

et al. 2008

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Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel þ ); ALT positive; ALTÀ/TelÀ. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel þ compared to ALTÀ/TelÀ samples and increased hTERT in Tel þ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients.

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“…Telomerase is not active in quiescent somatic cells but is usually required for cell immortalization and plays an important role in oncogenesis. [1][2][3][4][5][6][7] Using the telomere repeat amplification protocol (TRAP), a PCR-based assay described by Kim et al 8 in 1994 telomerase activity has been demonstrated in over 80% of malignant tumors from various organs. 9 Thus, telomerase activity might play a role as a diagnostic marker of malignancy.…”

mentioning

confidence: 99%

Telomere repeat amplification protocol (TRAP) in situ reveals telomerase activity in three cell types in effusions: malignant cells, proliferative mesothelial cells, and lymphocytes

Zendehrokh

Dejmek

2005

Modern Pathology

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Telomerase Repeat Amplification Protocol (TRAP) in situ was performed on cytospin preparations from 65 effusions from the serous cavities (45 pleural and 19 ascitic fluids and one pericardial fluid) submitted for routine diagnosis and the results were correlated to cytological morphology. Three types of cells with nuclear fluorescence were identified: malignant cells, hyperplastic mesothelial cell and lymphocytes. Of 38 cytologically malignant effusions, 12 showed strong reactivity in all malignant cells, three strong reactivity in part of the malignant population, whereas 12 showed moderate reactivity in the whole and five in part of the malignant population, respectively. In five malignant effusions weak reactivity was found in all (one case) and in scattered (four cases) malignant cells. Two effusions contained telomerase-negative malignant cells. Two pleural and two ascitic fluids contained proliferative mesothelial cells with weak or, in one case, moderate reactivity. Lymphocytes usually showed weak telomerase activity. Telomerase was expressed in almost all malignant tumours metastatic to serous cavities. Heterogeneity in tumour populations was demonstrated, which may have diagnostic implications, especially in cytology. Weak or moderate reactivity was found in lymphocytes and in some mesothelial proliferations and may explain the low specificity for malignancy sometimes obtained with the TRAP extract method. The weak reactivity found in lymphocytes may reduce the specificity when the extract method is used but causes no diagnostic problem with the TRAP in situ method.

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Human Telomerase and Its Regulation

Cited by 761 publications

References 258 publications

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

Telomere repeat amplification protocol (TRAP) in situ reveals telomerase activity in three cell types in effusions: malignant cells, proliferative mesothelial cells, and lymphocytes

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