Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA

doi:10.1016/S0092-8674(01)80006-4

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Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA

Journal Article•DOI•

Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA

Maria A. Blasco¹, Maria A. Blasco², Han Woong Lee³, M. Prakash Hande⁴, Enrique Samper¹, Peter M. Lansdorp⁴, Ronald A. DePinho⁵, Carol W. Greider², Carol W. Greider⁶ - Show less +5 more•Institutions (6)

Spanish National Research Council¹, Cold Spring Harbor Laboratory², Yeshiva University³, University of British Columbia⁴, Albert Einstein College of Medicine⁵, Johns Hopkins University⁶

03 Oct 1997-Cell (Cell Press)-Vol. 91, Iss: 1, pp 25-34

TL;DR: Results indicate that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice.

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About: This article is published in Cell.The article was published on 1997-10-03 and is currently open access. It has received 2066 citations till now. The article focuses on the topics: Telomerase RNA component & Telomerase reverse transcriptase.

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Journal Article•DOI•

The Hallmarks of Aging

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Carlos López-Otín¹, Maria A. Blasco, Linda Partridge², Manuel Serrano, Guido Kroemer² - Show less +1 more•Institutions (2)

University of Oviedo¹, Max Planck Society²

06 Jun 2013-Cell

TL;DR: Nine tentative hallmarks that represent common denominators of aging in different organisms are enumerated, with special emphasis on mammalian aging, to identify pharmaceutical targets to improve human health during aging, with minimal side effects.

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9,980 citations

Cites background from "Telomere Shortening and Tumor Forma..."

...Thus, mice with shortened or lengthened telomeres exhibit decreased or increased lifespans, respectively (Armanios et al., 2009; Blasco et al., 1997; Herrera et al., 1999; Rudolph et al., 1999; Tomás-Loba et al., 2008)....
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...Thus, mice with shortened or lengthened telomeres exhibit decreased or increased lifespans, respectively (Armanios et al., 2009; Blasco et al., 1997; Herrera et al., 1999; Rudolph et al., 1999; Tomás-Loba et al., 2008)....
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Book•

Pathology and genetics of tumours of the urinary system and male genital organs

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John N. Eble

01 Jan 2004

3,111 citations

Journal Article•DOI•

TRF2 Protects Human Telomeres from End-to-End Fusions

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Bas van Steensel¹, Agata Smogorzewska¹, Titia de Lange¹•Institutions (1)

Rockefeller University¹

06 Feb 1998-Cell

TL;DR: It is shown that the human telomeric protein TRF2 plays a key role in the protective activity of telomeres, and the results raise the possibility that chromosome end fusions and senescence in primary human cells may be caused by loss byTRF2 from shortenedtelomeres.

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1,708 citations

Cites background from "Telomere Shortening and Tumor Forma..."

...In those cases, telomeric DNA is usually not detectable at thesome end fusions in anaphase and metaphase cells likely represents an underestimate of the actual number site of fusion (Blasco et al., 1997)....
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Journal Article•DOI•

Telomeres and human disease: ageing, cancer and beyond

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Maria A. Blasco

01 Aug 2005-Nature Reviews Genetics

TL;DR: Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease.

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Abstract: Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.

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1,572 citations

Journal Article•DOI•

Cellular Senescence in Cancer and Aging

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Manuel Collado, Maria A. Blasco, Manuel Serrano

27 Jul 2007-Cell

TL;DR: Cellular senescence, a state of irreversible growth arrest, can be triggered by multiple mechanisms including telomere shortening, the epigenetic derepression of the INK4a/ARF locus, and DNA damage, and together these mechanisms limit excessive or aberrant cellular proliferation.

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1,537 citations

Cites background from "Telomere Shortening and Tumor Forma..."

...Further reinforcing the link between the telomere clock and aging, mice deficient in telomerase activity have short telomeres and age prematurely (Blasco et al., 1997; Lee et al., 1998)....
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...The generation of telomerase-deficient mice demonstrated that telomerase is the main cellular activity responsible for maintaining telomere length (Blasco et al., 1997)....
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References

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Journal Article•DOI•

Specific association of human telomerase activity with immortal cells and cancer

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Nam Woo Kim¹, Mieczyslaw A. Piatyszek², Karen R. Prowse¹, Calvin B. Harley¹, Michael D. West¹, Peter L. C. Ho¹, Gina M. Coviello¹, Woodring E. Wright², Scott L. Weinrich¹, Jerry W. Shay - Show less +6 more•Institutions (2)

Geron Corporation¹, University of Texas Southwestern Medical Center²

23 Dec 1994-Science

TL;DR: A highly sensitive assay for measuring telomerase activity was developed in this paper, which showed that telomerases appear to be stringently repressed in normal human somatic tissues but reactivated in cancer, where immortal cells are likely required to maintain tumor growth.

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Abstract: Synthesis of DNA at chromosome ends by telomerase may be necessary for indefinite proliferation of human cells. A highly sensitive assay for measuring telomerase activity was developed. In cultured cells representing 18 different human tissues, 98 of 100 immortal and none of 22 mortal populations were positive for telomerase. Similarly, 90 of 101 biopsies representing 12 human tumor types and none of 50 normal somatic tissues were positive. Normal ovaries and testes were positive, but benign tumors such as fibroids were negative. Thus, telomerase appears to be stringently repressed in normal human somatic tissues but reactivated in cancer, where immortal cells are likely required to maintain tumor growth.

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7,033 citations

"Telomere Shortening and Tumor Forma..." refers background or methods in this paper

...…of Medicine Telomerase activity is detectable in 80% to 90% ofUniversity of British Columbia human tumor samples, while the normal adjacent tissueVancouver, British Columbia usually lacks measurable activity (reviewed in Harley etCanada al., 1994; Kim et al., 1994, Shay and Bacchetti, 1997)....
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...Telomerase activity was measured using a modified version (Blasco et al., 1995) of the TRAPtional evidence besides the presence of high levels of assay (Kim et al., 1994) as well as the conventional telomerase assaytelomerase will be needed to verify this in the light of (Prowse et al., 1993)....
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...…blots of total RNA isolated from mouse The TRAP assay for telomerase activity is based onembryonic fibroblasts (MEFs) showed that the mTR tranthe PCR amplification of telomerase products con-script was not detectable in total RNA derived from taining the sequence (TTAGGG)n (Kim et al., 1994)....
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Journal Article•DOI•

Telomeres shorten during ageing of human fibroblasts.

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Calvin B. Harley¹, A B Futcher², Carol W. Greider²•Institutions (2)

McMaster University¹, Cold Spring Harbor Laboratory²

31 May 1990-Nature

TL;DR: The amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo.

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Abstract: The terminus of a DNA helix has been called its Achilles' heel. Thus to prevent possible incomplete replication and instability of the termini of linear DNA, eukaryotic chromosomes end in characteristic repetitive DNA sequences within specialized structures called telomeres. In immortal cells, loss of telomeric DNA due to degradation or incomplete replication is apparently balanced by telomere elongation, which may involve de novo synthesis of additional repeats by novel DNA polymerase called telomerase. Such a polymerase has been recently detected in HeLa cells. It has been proposed that the finite doubling capacity of normal mammalian cells is due to a loss of telomeric DNA and eventual deletion of essential sequences. In yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells. Here, we show that the amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. It is not known whether this loss of DNA has a causal role in senescence.

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5,454 citations

"Telomere Shortening and Tumor Forma..." refers background in this paper

...Early passage MEF cultures from G1 mTR1/1 and mTR1/2 and G1, G2, G3, G4, and (Cooke and Smith, 1986; Harley et al., 1990; Hastie et al., 1990)....
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...…derived from wild-type and merase activity, telomeres shorten by about 100 bp per mTR2/2 G2, G4, and G6 animals, and the fluorescence cell division (Harley et al., 1990; Counter et al., 1992). intensity on all chromosome ends from 25 or more metaThe terminal restriction fragment (TRF) containing…...
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...These results indicate that telomerase activity per (Harley et al., 1990; Allsopp et al., 1992; Prowse and Greider, 1995), would generate a 3-to-6-kb loss in these is not essential for transformed cells to form tumors in nude mice. male germline and a 1-to-3-kb loss in the female germline....
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Journal Article•DOI•

Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a

[...]

Manuel Serrano¹, Athena W. Lin¹, Mila E. McCurrach¹, David Beach², David Beach¹, Scott W. Lowe¹ - Show less +2 more•Institutions (2)

Cold Spring Harbor Laboratory¹, Howard Hughes Medical Institute²

07 Mar 1997-Cell

TL;DR: It is shown that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest, and that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an onCogenic stimulus.

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4,770 citations

"Telomere Shortening and Tumor Forma..." refers background in this paper

...Telomerase activity in normal and malignant murine tissues. ( Serrano et al., 1997 )....
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...(Serrano et al., 1997)....
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Journal Article•DOI•

Identification of a specific telomere terminal transferase activity in tetrahymena extracts

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Carol W. Greider¹, Elizabeth H. Blackburn¹•Institutions (1)

University of California, Berkeley¹

01 Dec 1985-Cell

TL;DR: It is proposed that the novel telomere terminal transferase is involved in the addition of telomeric repeats necessary for the replication of chromosome ends in eukaryotes.

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3,242 citations

Journal Article•DOI•

Structure and function of telomeres

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Elizabeth H. Blackburn

18 Apr 1991-Nature

TL;DR: The DNA of telomeres—the terminal DNA-protein complexes of chromosomes—differs notably from other DNA sequences in both structure and function, and has been shown to be essential for telomere maintenance and long-term viability.

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Abstract: The DNA of telomeres--the terminal DNA-protein complexes of chromosomes--differs notably from other DNA sequences in both structure and function. Recent work has highlighted its remarkable mode of synthesis by the ribonucleoprotein reverse transcriptase, telomerase, as well as its ability to form unusual structures in vitro. Moreover, telomere synthesis by telomerase has been shown to be essential for telomere maintenance and long-term viability.

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3,139 citations

"Telomere Shortening and Tumor Forma..." refers background in this paper

...Cell, Vol. 91, 25–34, October 3, 1997, Copyright 1997 by Cell Press Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA Marı́a A. Blasco,1,3,7 Han-Woong Lee,2,7 during DNA replication (reviewed in Blackburn, 1991)....
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