Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT)

Poole, Joseph; Andrews, Lori B.; Tollefsbol, Trygve O.

doi:10.1016/s0378-1119(01)00440-1

Cited by 260 publications

(229 citation statements)

References 92 publications

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“…Unlike humans, in which the expression of hTERT is limited to a small number of normal tissues, 25 mTERT expression is widely expressed at low levels in many adult tissues. 52 Despite the difference in expression pattern, adenoviral vectors using the hTERT promoter to drive LacZ or HSV-thymidine kinase genes had undetectable transgene expression in the livers of mice, 28,30,33 suggesting that activity of the hTERT promoter is low in normal mouse liver. This was not attributable to the inability of the hTERT promoter to use the mouse transcriptional machinery, since LacZ expression was seen in the mouse lung carcinoma cell line M109.…”

Section: Discussionmentioning

confidence: 99%

“…4 The hTERT gene has been previously shown to be selectively expressed in the majority of human cancers. [23][24][25][26][27][28] Furthermore, the hTERT promoter has been shown to confer tumor-selective expression of the linked gene in plasmids and Ad constructs. [28][29][30][31][32][33] Oncolytic adenoviruses utilizing the hTERT promoter to control Ad early region genes have also been previously described.…”

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confidence: 99%

“…[23][24][25][26][27][28] Furthermore, the hTERT promoter has been shown to confer tumor-selective expression of the linked gene in plasmids and Ad constructs. [28][29][30][31][32][33] Oncolytic adenoviruses utilizing the hTERT promoter to control Ad early region genes have also been previously described. [34][35][36] By using both the E2F-1 promoter and the hTERT promoter to control different early region genes in the same Ad vector, we have constructed an oncolytic Ad which is active in a broad panel of tumor types and is safe and effective when delivered systemically.…”

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Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

et al. 2004

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A potentially promising treatment of metastatic cancer is the systemic delivery of oncolytic adenoviruses. This requires engineering viruses which selectively replicate in tumors. We have constructed such an oncolytic adenovirus, OAS403, in which two early region genes are under the control of tumor-selective promoters that play a role in two key pathways involved in tumorigenesis. The early region E1A is controlled by the promoter for the E2F-1 gene, a transcription factor that primarily upregulates genes for cell growth. The E4 region is under control of the promoter for human telomerase reverse transcriptase, a gene upregulated in most cancer cells. OAS403 was evaluated in vitro on a panel of human cells and found to elicit tumor-selective cell killing. Also, OAS403 was less toxic in human hepatocyte cultures, as well as in vivo when compared to an oncolytic virus that lacked selective E4 control. A single intravenous injection of 3 Â 10 12 vp/kg in a Hep3B xenograft mouse tumor model led to significant antitumor efficacy. Additionally, systemic administration in a pre-established LNCaP prostate tumor model resulted in over 80% complete tumor regressions at a tolerable dose. Vector genome copy number was measured in tumors and livers at various times following tail vein injection and showed a selective time-dependent increase in tumors but not livers over 29 days. Furthermore, efficacy was significantly improved when OAS403 treatment was combined with doxorubicin. This virus holds promise for the treatment of a broad range of human cancers including metastatic disease.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

et al. 2004

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“…Transcriptional repression of hTERT early in human development (in utero), post-transcriptional processing events, epigenetic changes in the gene, and perhaps other factors which prevent functional telomerase formation, are responsible for the`mortalization' of normal somatic cells (Cong and Bachetti, 2000;Dessain et al, 2000;Poole et al, 2001;Ulaner and Giudice, 1997;Ulaner et al, 1998;Wright et al, 1996). Multiple pathways for stringent repression or controlled regulation of telomerase probably account for the extreme rarity of spontaneous immortalization of normal human cells.…”

Section: Cancer Growth Control and Cell Immortalitymentioning

confidence: 99%

Telomerase is not an oncogene

2002

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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 con®rmed 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 speci®city 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 clari®es the di erence 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.

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“…Recent experimental studies have shown that reexpression of hTERT in normal human somatic cells can reconstitute telomerase activity and extend their replicative life span beyond crisis, the last-known proliferative blockade to cellular immortality (32). Telomerase reactivation has therefore been associated with the appearance of immortal cell populations, a crucial event in human carcinogenesis (33).…”

Section: Normal Laryngeal Epithelium and Simple And Abnormal Hyperplasiamentioning

confidence: 99%

Telomerase Reactivation Is an Early Event in Laryngeal Carcinogenesis

et al. 2003

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The exact role and timing of reactivation of telomerase, a key enzyme implicated in cellular immortalization and transformation in the multistep process of laryngeal carcinogenesis, is still unknown. We attempted to (1) determine that quantitative differences exist in the levels of telomerase catalytic subunit (hTERT) mRNA expression among different grades of laryngeal epithelial abnormalities classified according to the Ljubljana classification; (2) determine that telomerase reactivation is an important, most probably early event in laryngeal carcinogenesis; and (3) analyze whether the relative quantity of hTERT mRNA can be used as a molecular biomarker in the early detection of precancerous lesions. The relative quantity of hTERT mRNA, expressed as an hTERT index, was analyzed in 140 frozen laryngeal tissue specimens representing different morphological stages of laryngeal carcinogenesis by using a commercially available LightCycler Telo TAGGG hTERT Quantification kit. The presence and relative quantity of hTERT mRNA in laryngeal epithelium increases progressively with the degree of epithelial abnormalities. hTERT mRNA was detectable in 1/15 normal laryngeal epithelia (7%, mean hTERT index 0.02), 3/15 simple hyperplasias (20%, mean hTERT index 0.09), 10/27 abnormal hyperplasias (37%, mean hTERT index 0.18), 9/12 atypical hyperplasias (75%, mean hTERT index 0.74), 8/9 intraepithelial carcinomas (89%, mean hTERT index 1.82), and 53/62 invasive laryngeal squamous cell carcinomas (85%, mean hTERT index 2.51). Statistical analysis revealed two groups of laryngeal epithelial changes with significant differences in the levels of hTERT mRNA expression (P < .0033): (1) normal and reactive hyperplastic laryngeal epithelium (simple and abnormal hyperplasia) and (2) atypical hyperplasia (precancerous lesion), intraepithelial and invasive laryngeal squamous cell carcinoma. The results of the present study suggest that telomerase reactivation is an early event in laryngeal carcinogenesis, detectable already at the stage of precancerous laryngeal epithelial changes. Nevertheless, other genetic abnormalities appear to be necessary for progression of these epithelial abnormalities toward invasive laryngeal squamous cell carcinoma.

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Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT)

Cited by 260 publications

References 92 publications

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

Telomerase is not an oncogene

Telomerase Reactivation Is an Early Event in Laryngeal Carcinogenesis

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