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Luis 22.
User deleted
Come ben saprete, l'enzima telomerasi è in grado di impedire l'accorciamento dei telomeri, durante la replicazione.
Vari studi hanno dimostrato la relazione tra l'accorciamento dei telomeri (cosa normale per le cellule somatiche, dove la telomerasi non è attiva) e l'invecchiamento.
Ma non solo: si è osservato che nelle cellule cancerogene, si ha l'attivazione della telomerasi, come nelle cellule staminali.
Questo causa il mancato accorciamento dei telomeri, anzi in alcuni casi anche l'allungamento, se l'enzima è iperattivo.
Molti farmaci ora cercheranno anche questa via per sconfiggere il cancro.
Voi cosa ne pensate? Sembra quasi così sottile la linea che separa il mancato invecchiamento dal cancro..... -
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Ottimo Thread Luis! 
Ho letto anche io informazioni simili in merito alla Telomerasi e della relazione tra lunghezza dei telomeri-invecchiamento-cancro. Faccio una ricerca nei miei "archivi" e domani inserirò qualche documento.
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Ecco, io avevo questo, spero che funzioni, è la prima volta che faccio un upload nel mio forum. è un file in formato .rtf
File Allegato
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domani aggiornerò il post con nuovi documenti
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Articoli sui telomeri in inglese:
Telomere Functions. A Review
Immortalized Cells with No Detectable Telomerase Activity. A Review
(fonte: University of Moscow)
Edited by tursiops - 1/3/2005, 15:40. -
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Review
Telomerase is not an oncogene
Calvin B Harley
Geron Corporation, Menlo Park, California, CA 94025, USA
Correspondence to: C B Harley, Geron Corporation, 230 Constitution Drive, Menlo Park, California, CA 94025, USA; E-mail: [email protected]
Abstract
In the decade since the telomere hypothesis of cellular aging was proposed, the two essential genes for human telomerase were cloned and characterized, allowing experimental proof of the causal relationships between telomere loss and replicative senescence, and telomerase activation and immortalization. These relationships were established using a variety of cultured human cell types from both normal and tumor tissues, and were largely confirmed in the telomerase knockout mouse. Taken together, the data provide strong support for the potential utility of telomerase detection and inhibition for cancer, and telomerase activation for degenerative diseases. The specificity of the promoter for the telomerase catalytic gene and the antigenicity of the protein product, hTERT, provide additional strategies for killing telomerase-positive tumor cells. Unfortunately, the strong link between telomerase and cancer has led some to confuse telomerase activation with cancer, and others to overstate the cancer risk of telomerase activation therapies for degenerative diseases. This review clarifies the difference between telomerase, which does not cause growth deregulation, and oncogenes, which do. It also addresses the concept of telomerase repression as a tumor suppressor mechanism early in life, with detrimental tissue degeneration and tumor-promoting consequences late in life. This extended view of the telomere hypothesis helps explain how telomerase inhibition can be therapeutic in cancer patients, while controlled telomerase activation for degenerative diseases may actually reduce, rather than increase, the frequency of age-related tumorigenesis.
Oncogene (2002) 21, 494-502 DOI: 10.1038/sj/onc/1205076
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Review
Telomeres, aging and cancer: In search of a happy ending
Sahn-ho Kim, Patrick Kaminker and Judith Campisi
Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California, CA 94720, USA
Correspondence to: J Campisi, Lawrence Berkeley National Laboratory, Mailstop 84-171, 1 Cyclotron Road, Berkeley, CA 94720, USA; E-mail: [email protected]
Abstract
Telomeres are distinctive structures, composed of a repetitive DNA sequence and associated proteins, that cap the ends of linear chromosomes. Telomeres are essential for maintaining the integrity and stability of eukaryotic genomes. In addition, under some circumstances, telomeres can influence cellular gene expression. In mammals, the length, structure, and function of telomeres have been proposed to contribute to cellular and organismal phenotypes associated with cancer and aging. Here, we discuss what is known about the basis for the links between telomeres, aging and cancer, and some of the known and proposed consequences of telomere dysfunction and maintenance for mammalian cells and organisms.
Oncogene (2002) 21, 503-511 DOI: 10.1038/sj/onc/1205077
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Review
Telomere maintenance without telomerase
Victoria Lundblad
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, TX 77030, USA
Correspondence to: V Lundblad, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, TX 77030, USA. E-mail: [email protected]
Abstract
Recombination-dependent maintenance of telomeres, first discovered in budding yeast, has revealed an alternative pathway for telomere maintenance that does not require the enzyme telomerase. Experiments conducted in two budding yeasts, S. cerevisiae and K. lactis, have shown recombination can replenish terminal G-rich telomeric tracts that would otherwise shorten in the absence of telomerase, as well as disperse and amplify sub-telomeric repeat elements. Investigation of the genetic requirements for this process have revealed that at least two different recombination pathways, defined by RAD50 and RAD51, can promote telomere maintenance. Although critically short telomeres are very recombinogenic, recombination among telomeres that have only partially shortened in the absence of telomerase can also contribute to telomerase-independent survival. These observations provide new insights into the mechanism(s) by which recombination can restore telomere function in yeast, and suggest future experiments for the investigation of potentially similar pathways in human cells.
Oncogene (2002) 21, 522-531 DOI: 10.1038/sj/onc/1205079
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Review
Telomerase inhibition, oligonucleotides, and clinical trials
David R Corey1,2
1Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, TX 75390-9041, USA
2Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, TX 75390-9041, USA
Correspondence to: D R Corey, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas, TX 75390-9041, USA; E-mail: [email protected]
Abstract
Telomerase is expressed in most types of tumors but not in most somatic cells. This observation has led to two hypotheses; (i) telomerase activity is necessary for the proliferation of cancer cells; and (ii) telomerase inhibitors are a powerful strategy for cancer chemotherapy. Testing the latter hypothesis requires the development of potent and selective inhibitors of telomerase and their testing in clinical trials. Assaying the efficacy of telomerase inhibitors will not be simple because telomere erosion will be slow and antiproliferative effects will probably require weeks to become apparent. This review will describe the properties of 2'-O-alkyl oligonucleotide inhibitors of telomerase. Oligonucleotides that block expression of other cancer targets have favorable pharmacokinetic properties and are already in clinical trials. This experience is likely to facilitate clinical trials of anti-telomerase oligomers.
Oncogene (2002) 21, 631-637 DOI: 10.1038/sj/onc/1205063
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Review
Clinical utility of telomerase in cancer
Eiso Hiyama1 and Keiko Hiyama2
1Department of General Medicine, Hiroshima University, Faculty of Medicine, School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Hiroshima, Japan
2Second Department of Internal Medicine, Hiroshima University, Faculty of Medicine, School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Hiroshima, Japan
Correspondence to: E Hiyama, Department of General Medicine, Hiroshima University, Faculty of Medicine, School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Hiroshima, Japan. E-mail: [email protected]
Abstract
This review will focus on the clinical utilities of telomerase for human cancer diagnosis. Much attention has been focused on detection of telomerase activity and its essential components (hTR and hTERT) in cancer and noncancerous tissues. Expression of hTR and hTERT is upregulated in almost all human malignant tumors but not in benign or normal tissues with the exception of germline cells, proliferative stem cells, activated lymphocytes, and certain benign tumors. Thus, telomerase is a useful marker for cancer diagnosis and in some instance as a prognostic indicator of outcome. Telomerase detection in cells derived from breast fine needle aspirates, bronchial washes, and pancreatic juices show high sensitivity and specificity for cancer detection. In tissue samples, the level of telomerase activity is a useful prognostic indicator in certain adult cancers such as gastric and colon cancers and in neuroblastomas. Immunohistochemical detection of hTERT will facilitate exact diagnosis of the telomerase positive cells and expand the application of telomerase in cancer diagnosis.
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Altri articoli, in inglese, inerenti la telomerasi possono essere letti qui:
ONCOGENE - NATURE
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Figure 1. Regulation of telomere length in normal and cancer cells by telomerase. (a) In normal somatic cells telomerase is absent. Every time a normal cell divides, the telomeric repeat sequence (depicted as a purple bar) is lost from the end of the chromosome. Eventually, after many cell divisions, the gradual erosion of the telomere is sensed by the cell (an orange flag on the chromosome in the diagram depicts this event) and, when the telomeres reach a critically short length (red flag), a cell-signalling pathway initiates the senescence programme, resulting in a cessation of cellular proliferation. (b) In cancer cells, the expression of telomerase allows the senescence program to be bypassed (Refs 4, 7). Once activated, telomerase maintains telomeres at a length compatible with cell proliferation through the addition of telomere repeat sequences. Thus, the cancer cell becomes immortal
(fonte: Expert Reviews in Molecular Medicine © Cambridge University Press ISSN 1462-3994 )Attached Image
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Figure 3. The potential effects of telomerase inhibition over time on telomere length and proliferative capacity in cancer cells compared with normal human germ cells and stem cells. Both human germ cells and stem cells are considered to be telomerase-positive or competent to express telomerase, and so inhibition of telomerase should affect telomere length in these cells. However, tumour cells frequently have shorter telomeres than telomerase-competent normal cells and would therefore be expected to reach a critically short telomere length, leading to growth arrest or apoptosis, at an earlier stage
Expert Reviews in Molecular Medicine © Cambridge University Press ISSN 1462-3994
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Figure 4. Clinical application of telomerase inhibitors. The classic action of telomerase inhibitors will be to cause erosion of telomeric sequence over several cell divisions until critically short telomeres signal senescence and cell death to the cancer cell (a). Thus, on administration, the cancer volume might initially continue to increase prior to the desired therapeutic reduction in tumour volume (this is known as the lag phase). Therefore, telomerase inhibitors are likely to have their greatest clinical impact in minimal disease states, for example as maintenance therapy after tumour debulking by chemotherapy, as this would allow time for telomerase agents to have effect. Telomerase inhibitors will work only on telomerase-positive cells. Thus, telomerase-negative tumours (either mortal tumours or tumours that maintain their telomeres by alternative mechanisms to telomerase – i.e. ALT mechanisms) will be resistant to telomerase inhibitors (b). There are now numerous assays to test for telomerase activity, enabling tumours to be tested for suitability for telomerase therapy. However, these assays might fail to detect mixed populations of telomerase-positive and telomerase-negative cells in the tumour population ©. In this situation, although the tumour might be predicted to respond to telomerase inhibitors, only the telomerase-positive fraction of tumour cells will be targeted, leaving the ALT cells to repopulate the tumour mass
Expert Reviews in Molecular Medicine © Cambridge University Press ISSN 1462-3994
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Figure 2. Schematic representation of the composition of telomeric complexes, telomerase and proteins implicated in cellular signalling from the telomere (telomere repair). Telomerase comprises the RNA component hTR, which includes the template for telomere DNA synthesis, and the protein catalytic component hTERT. Additional molecules have been implicated in regulating the in vivo activity of hTR–hTERT and the maintenance of telomere structure. For example, the proteins TRF1, TRF2, tankyrase, TIN2, RAP1 (not shown) and POT1 are all involved in interacting with the telomere and might regulate the opening and closing of the free telomere end and access to the telomere by other protein complexes such as telomerase. A variety of proteins and ribonucleoproteins including HSP90, as well as DKC1, L22, P23 and GAR1 (not shown), might also assist telomerase assembly and facilitate interactions between telomerase and the telomere. Other proteins such as MRE11A, NBS1, KU70, KU80, DNAPK (not shown) and ATM might function in the detection of short telomeres and trigger DNA-damage response pathways or the repair of telomere sequences. Abbreviations and more information on each component can be found in Table 1 and the hyperlinks embedded therein
Expert Reviews in Molecular Medicine © Cambridge University Press ISSN 1462-3994
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Telomerasiaccorciamento telomeri |
