1: Int J Cancer. 2007 May 1;120(9):1835-41.


Telomerase expression in lung preneoplasia and neoplasia.

Lantuéjoul S, Salon C, Soria JC, Brambilla E.

Department of Pathology and Lung Cancer Research Group INSERM U 578, Institut A Bonniot, CHU Michallon, Grenoble, France.

Telomeres are specialized structures at eukaryotic chromosomes ends, which role is to prevent them from degradation, end to-end fusion and rearrangement. However, they shorten after each cellular division because of an incomplete DNA replication, acting in normal somatic cells as a mitotic clock for permanent proliferation arrest or senescence entry. Short telomeres are perceived as damaged DNA leading to p53/ATM pathway activation. In tumoral cells, a ribonucleoprotein complex termed telomerase enables telomere elongation. This complex, composed of 2 main components, the telomerase RNA component or hTR, the RNA template for telomere synthesis, and telomerase reverse transcriptase, the catalytic subunit, is reactivated in the majority of cancers, including those of the lung. In this review, we briefly present the main results on telomerase expression in various histological types of lung carcinoma and in bronchial carcinogenesis along with telomere attrition. Inhibition of one of the main components of the enzyme or limitation of telomere access by telomerase represent novel targets for cancer therapies and chemoprevention in high risk patients of lung cancer. (c) 2007 Wiley-Liss, Inc.

Publication Types:
Review

PMID: 17311257 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

2: Acta Haematol. 2004;111(3):125-31.


Telomere length variation and telomerase activity expression in patients with congenital and acquired aplastic anemia.

Polychronopoulou S, Koutroumba P.

Department of Pediatric Hematology/Oncology, Aghia Sophia Children's Hospital, Athens, Greece. sophpol@otenet.gr

Telomeres represent the nucleoprotein tails of chromosomes that get shortened with each cell division. When the telomere length reaches a critical point, cell senescence and death occur. Telomerase is a reverse transcriptase that counteracts telomere loss by adding telomeric sequences. In patients with acquired aplastic anemia, the mean telomere length (TRF) of peripheral blood leukocytes is generally short when compared to normal controls, without it being clear whether a relationship between TRF and disease severity exists. Additionally, increased telomerase activity (TA) is found in the bone marrow mononuclear cell population (MNCs) of aplastic anemia patients, especially in the chronic form of the disease. Fanconi anemia (FA) patients generally demonstrate increased TA and short telomeres in peripheral blood MNCs, a fact attributed to the high turnover of hematopoietic progenitor cells in combination with direct breakages at telomeric sequences. Furthermore, a strong correlation has been shown between TRF and the severity of aplastic anemia, but not with FA evolution towards myelodysplastic syndrome or acute myeloblastic leukemia. In respect of dyskeratosis congenita (DC), a disease of either X-linked or autosomal dominant/recessive inheritance which is characterized by premature ageing of highly regenerative tissues, studies have been carried out in order to elucidate whether the X-linked DC is caused by a defect in ribosomal RNA processing and/or telomere maintenance. Finally, the direct genetic link established between DC pathogenesis and short telomeres may lead to the development of new therapeutic protocols for diseases characterized by short telomere length and subsequent genomic instability. Copyright 2004 S. Karger AG, Basel

Publication Types:
Review

PMID: 15034232 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

3: Int J Oncol. 2002 Aug;21(2):265-72.


Expression of telomerase genes in thyroid carcinoma.

Hoang-Vu C, Boltze C, Gimm O, Poremba C, Dockhorn-Dworniczak B, Köhrle J, Rath FW, Dralle H.

Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Germany. hoang-vu@medizin.uni-halle.de

Telomerase (T) is a ribonucleoprotein complex that includes the telomerase RNA component (hTR), telomerase associated protein (TP1) and the telomerase catalytic subunit (hTERT). Telomerase has been shown in stem cells and found to be activated in tumor tissues and immortalized cells. We wanted to test whether the expression of the telomerase complex subunits correlate with the enzyme activity in human thyroid tissue. Hence, we determined the expression of hTERT, hTR and TP1 mRNA by RT-PCR and compared the results to telomerase activity as detected by the telomeric repeat amplification protocol (TRAP) assay. Fifteen benign goiters (G), 11 follicular carcinomas (FTC) including 2 oncocytic follicular carcinomas (also called Hurthle cell carcinoma, oFTC), 12 papillary carcinomas (PTC) including 3 microcarcinomas (mPTC), and 12 undifferentiated anaplastic thyroid carcinomas (UTC) were investigated. Experienced pathologists performed histological and pTNM classification in each specimen. RT-PCR analysis revealed that TP1 was ubiquitously expressed in all G and carcinomas. hTR was expressed in 4 out of 15 G, in 2 out of 3 mPTC, in 5 out of 9 PTC, in 5 out of 9 FTC, in all oFTC and in 9 out of 12 UTC samples. Regarding all carcinomas, no statistically significant correlation was observed between hTR-expression and tumor stage, lymph node or distant metastasis. hTERT-expression was associated with malignancy and tumor stage. All mPTC and 13 out of 15 G did not express hTERT, whereas all samples of pT3-4 tumor stage of FTC, PTC, UTC and all oFTC were positive for hTERT. No telomerase activity could be detected in G. Telomerase activity in carcinoma was only measurable in tissues that expressed the catalytic subunit hTERT. Our data indicate that telomerase activity is up-regulated in neoplastic cells. In contrast to TP1 and hTR, hTERT and telomerase activity may be of help in identifying invasive tumors and may be additional markers for classification of benign goiter and malignant thyroid carcinoma.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 12118320 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

4: Seikagaku. 2002 Mar;74(3):233-7.


[Mechanism for telomerase gene expression]

[Article in Japanese]

Nozawa K.

Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585.

Publication Types:
Review

PMID: 11974917 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

5: Springer Semin Immunopathol. 2002;24(1):23-33.


Regulation of telomerase expression in human lymphocytes.

Weng NP.

Laboratory of Immunology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Box 21, Baltimore, MD 21224, USA.

The function of lymphocytes is highly dependent on the ability of cell to divide. Among the various factors that regulate this cellular process, telomerase-dependent maintenance of telomere length has recently drawn considerable attention. Unlike most normal human somatic cells that express telomerase only during development but not after differentiation, lymphocytes express telomerase during development and retain the ability to express telomerase after maturation in response to antigenic challenge. How telomerase is regulated and its precise role in lymphocytes is not fully understood. The recent progress in characterizing regulation of telomerase expression in human lymphocytes is discussed.

Publication Types:
Review

PMID: 11974579 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

6: Methods Mol Biol. 2002;191:65-81.


Analysis of telomerase RNA gene expression by in situ hybridization.

Keith WN, Sarvesvaran J, Downey M.

CRC Department of Medical Oncology, University of Glasgow, CRC Beatson Labs, Glasgow, UK.

Publication Types:
Review

PMID: 11951610 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

7: J Clin Immunol. 2000 Jul;20(4):257-67.


The role of telomerase expression and telomere length maintenance in human and mouse.

Weng NP, Hodes RJ.

National Institute on Aging and National Cancer Institute, Bethesda, Maryland 20892, USA.

The molecular regulation of telomere length has been well elucidated by a series of elegant studies over the past decade. More recently, experimental evidence has accrued that addresses the challenging question of if and how telomere length regulation may contribute to normal human aging or to human disease. Recent studies in mice have provided a mammalian precedent indicating that telomerase deficiency can lead to in vivo dysfunction, most probably as a consequence of progressive telomere shortening. In humans, the evidence that telomere shortening might lead to in vivo dysfunction is far less direct, although the recent description of telomerase deficiency and telomere shortening associated with the DKC syndrome is suggestive of such a link. Methodologies exist and continue to be developed that are increasingly capable of manipulating telomerase activity and telomere length in human cells. It remains to be determined whether scientifically rigorous and (equally important) medically ethical approaches will emerge to directly assess the ability of telomere length modulation to correct functional disorders of human cellular function ex vivo or more challenging still, in vivo.

Publication Types:
Review

PMID: 10939713 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

8: Oncogene. 1999 Dec 13;18(53):7676-80.


Alternative pathways for the extension of cellular life span: inactivation of p53/pRb and expression of telomerase.

Vaziri H, Benchimol S.

Stanford University School of Medicine, Department of Molecular Pharmacology, Edward's Building, 300 Pasteur Drive Stanford, California, CA 94305-5332, USA.

Telomere shortening may be one of several factors that contribute to the onset of senescence in human cells. The p53 and pRb pathways are involved in the regulation of cell cycle progression from G1 into S phase and inactivation of these pathways leads to extension of life span. Short dysfunctional telomeres may be perceived as damaged DNA and may activate these pathways, leading to prolonged arrest in G1, typical of cells in senescence. Inactivation of the p53 and pRb pathways, however, does not lead to cell immortalization. Cells that overcome senescence and have an extended life span continue to lose telomeric DNA and subsequently enter a second phase of growth arrest termed 'crisis'. Forced expression of telomerase in human cells leads to the elongation of telomeres and immortalization. The development of human cancer is frequently associated with the inactivation of the pRb and p53 pathways, attesting to the importance of senescence in restricting the tumor-forming ability of human cells. Cancer cells must also maintain telomere length and, in the majority of cases, this is associated with expression of telomerase activity.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10618707 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

9: Nippon Rinsho. 1998 May;56(5):1190-3.


[Analysis of expression of human telomerase RNA in gastric precancerous and cancerous lesions by using in situ mRNA hybridization]

[Article in Japanese]

Hiyama T, Yokozaki H, Kitadai Y, Tahara H, Yasui W, Tahara E.

First Department of Pathology, Hiroshima University School of Medicine.

We described the localization of human telomerase RNA (hTR) expression in human gastric precancerous and cancerous lesions by using in situ mRNA hybridization. Diffusely high hTR expression was found in all carcinoma and adenoma tissues. Partially high hTR expression was seen in 75% hyperplastic polyps, 47% complete-type intestinal metaplasia and 21% incomplete-type intestinal metaplasia. All chronic gastritis without intestinal metaplasia possessed normal levels of hTR expression. The expression of hTR was heterogeneous and infiltrating lymphoid cells also expressed high levels of hTR expression. Taken together, overexpression of hTR due to stem cell hyperplasia is an early event of carcinogenesis of the stomach.

Publication Types:
English Abstract
Review

PMID: 9613120 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

10: Eur J Cancer. 1997 Apr;33(5):792-800.


Telomere structure and telomerase expression during mouse development and tumorigenesis.

Kipling D.

Department of Pathology, University of Wales College of Medicine, Cardiff, U.K.

Mouse telomeres are on average longer than those of man, raising questions regarding the link between telomere loss and replicative senescence in mice and the requirement for telomerase activity for mouse cell immortalisation. However, the emerging data on telomerase activity during tumorigenesis in the mouse must be interpreted in the context of the very different structure of mouse telomeres. It will be argued here that the evidence for a casual link between telomere loss and replicative senescence is weak in the mouse, with the observed upregulation of telomerase activity in mouse tumours perhaps instead reflecting co-ordinated regulatory changes in tumour cells. Its absence would be consistent with evolutionary considerations, which hypothesise that such a link is an additional layer of control against tumour formation that has evolved in man. The very different genomic substrates for telomerase in humans and mice mean that the initial phenotype of a telomerase knock-out mouse does not necessarily critically address the existence of a link between telomerase and tumorigenesis in man.

Publication Types:
Review

PMID: 9282119 [PubMed - indexed for MEDLINE]