Disease relevance of Tep1

• Autosomal-dominant dyskeratosis congenita is associated with heterozygous mutations in telomerase [1].
• The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres implicate telomere attrition in the pathogenesis of Werner syndrome [2].
• These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of "telomerase therapy" for such diseases [3].
• Genes and pathways downstream of telomerase in melanoma metastasis [4].
• These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis [4].

High impact information on Tep1

• To examine the dosage effect of telomerase, we generated a line of mTR+/- mice on the CAST/EiJ background, which has short telomeres [1].
• Interbreeding of heterozygotes resulted in progressive telomere shortening, indicating that limiting telomerase compromises telomere maintenance [1].
• The progressive worsening of disease with decreasing telomere length suggests that short telomeres, not telomerase level, cause stem cell failure [1].
• These data suggest that telomerase can inhibit chromosomal instability [5].
• The phenotype of the telomerase null offspring was similar to that of the late generation parent, although only half of the chromosomes were short [6].

Chemical compound and disease context of Tep1

• Telomerase activity and 8-hydroxy-2'-deoxyguanosine levels in the liver were not significantly altered by exercise and/or sarcoma [7].
• Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity [8].

Biological context of Tep1

• The cDNA encodes a 2629 amino acid sequence and produces the TLP1 proteins p240 and p230 [9].
• ES cells deficient in mTep1 also showed no detectable alteration in telomerase activity or telomere length with increased passage in culture [10].
• A known Myc transcriptional target is the catalytic subunit of telomerase, Tert [11].
• Telomere elongation is carried out by telomerase, an RNA-dependent DNA polymerase which adds single-stranded TAGGGT repeats to the 3' ends of chromosomes [12].
• These results clearly demonstrate telomerase is activated in late stages of tumour progression, and show for the first time that the initial up regulation of telomerase RNA is an early event, concurrent with the hyperproliferation elicited by viral oncogenes [13].

Anatomical context of Tep1

• In vitro telomerase activity, however, is not altered in Adprt1-/- mouse fibroblasts [14].
• These 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 [15].
• Telomerase activity in germ cells is sufficient to prevent telomere shortening with age [16].
• Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential [17].
• In T cells, antigenic stimulation has been shown to result in a marked increase in the level of telomerase activity [18].

Associations of Tep1 with chemical compounds

• Moreover, treatment with L-t-C6-Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide [19].
• Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production [4].
• Here, we use telomerase-deficient mice, Terc(-/-), to study the impact of telomerase abrogation in response to treatment with the alkylating agent N-Methyl-N-Nitrosourea (MNU), a potent carcinogen in the mouse [20].
• Consequently glutathione concentration parallels telomerase activity [21].
• When cells are treated with buthionine sulfoximine, which decreases glutathione levels in cells, telomerase activity decreases by 60%, and cell growth is delayed [21].

Physical interactions of Tep1

• TIN2 is a negative regulator of telomere elongation that interacts with telomeric DNA repeat binding factor 1 (TRF1) and affects telomere length by a telomerase-dependent mechanism [22].

Regulatory relationships of Tep1

• We first demonstrated that Myc activates telomerase in the skin [11].
• Stem cell factor activates telomerase in mouse mitotic spermatogonia and in primordial germ cells [23].
• This gene (Acd) has recently been characterized as a novel component of the TRF1 protein complex that controls telomere elongation by telomerase [24].
• We have also identified mTR mutants that are able to inhibit wild type telomerase in vivo [25].
• Increased telomerase activity enhances the self-renewal ability of the Tert-overexpressing ESCs, improves their resistance to apoptosis, and increases their proliferation [26].

Other interactions of Tep1

• With Inv-MycERTAM x Terc-/- mice, we further showed that this telomerase activation is partially required to elicit a full hyperplastic Myc-induced response [11].
• Here, we describe the isolation and characterization of the catalytic subunit of mouse telomerase, mTERT (mouse telomerase reverse transcriptase), an essential protein component of the telomerase complex [27].
• Our data suggest that the induction of telomerase by Kitl may contribute to the self-renewing potential of male germ cells and of PGCs [23].
• Mice deficient in telomerase activity develop hypertension because of an excess of endothelin production [28].
• Thus, PARP-1 does not have a major role in telomere metabolism, not even in the context of telomerase deficiency [29].

Analytical, diagnostic and therapeutic context of Tep1

• Telomere shortening in human and mouse tissues and primary cell cultures may be due to the absence of telomerase activity [13].
• Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery [3].
• Telomeres shorten in hematopoietic cells, including hematopoietic stem cells (HSCs), during aging and after transplantation, despite the presence of readily detectable levels of telomerase in these cells [18].
• Together, these results imply that one role for telomerase in T cells may be to renew or extend replicative potential via the rejuvenation of telomere length [18].
• These results suggest that, contrary to the general assumption, telomerase actively promotes proliferation in cells that have sufficiently long telomeres and unravel potential risks of gene therapy for age-associated diseases based on telomerase upregulation [30].

References