Somatic cell telomerase activity

Telomeres in human chromosomes consist of tandem repeats of the sequence TTAGGG. In most adult somatic cells, telomerase activity is very low or absent. Even in... 

ITowever, most normal somatic cells lack telomerase. Consequently, upon every cycle of cell division when the cell replicates its DNA, about 50-nucleotide portions are lost from the end of each telomere. Thus, over time, the telomeres of somatic cells in animals become shorter and shorter, eventually leading to chromosome instability and cell death. This phenomenon has led some scientists to espouse a telomere theory of aging that implicates telomere shortening as the principal factor in cell, tissue, and even organism aging. Interestingly, cancer cells appear immortal because they continue to reproduce indefinitely. A survey of 20 different tumor types by Geron Corporation of Menlo Park, California, revealed that all contained telomerase activity. 

Telomerase is an enzyme in eukaryotes used to maintain the telomeres. It contains a short RNA template complementary to the DNA telomere sequence, as well as telomerase reverse transcriptase activity (hTRT). Telomerase is thus able to replace telomere sequences that would otherwise be lost during replication. Normally telomerase activity is present only in embryonic cells, germ (reproductive) cells, and stem cells, but not in somatic cells. 

Human telomerase is a structurally complex ribonucleoprotein that is responsible for the maintenance of telomeric DNA at the ends of chromosomes. Telomerase acts to synthesize and add a simple six-base motif (of TTAGGG in the human case) to the ends of the chromosomes, resulting in stable telomere length that would otherwise be gradually eroded after each cell replication. Active telomerase has been detected in a majority of human cancer, embryonic, and germline cells but not in normal somatic cells, with the exception of some stem cells, such as those involved in tissue renewal. 

Telomerase is normally active during embryogenesis, but is repressed in most somatic cells before or shortly after birth. Germline cells, activated lymphocytes, and other immortal cells show no shortening of telomere length and possess telomerase activity. Thus tumor cells should also show telomerase activity that can act as a specific marker of transformation. 

As often happens in these days of the human genome project, the human version hTERT) was found shortly thereafter [16, 17]. It was expressed in a variety of transformed cells but not detectable in primary cultures of human somatic cells, already giving a simple answer as to why telomerase activity was deficient in somatic cells. Thus, over a short time span, we went from having no telomerase protein to a whole family of TERTs (Telomerase Reverse Transcriptases). 

Germ-line cells and rapidly dividing somatic cells (e.g., stem cells) produce telomerase, but most human somatic cells lack telomerase. As a result, their telomeres shorten with each cell cycle. Complete loss of telomeres leads to end-to-end chromosome fusions and cell death. Extensive shortening of telomeres Is detected as a kind of DNA damage, with consequent stabilization and activation of p53 protein, leading to p53-trlggered apoptosis. 

Verbascoside is able to inhibit another enzyme related to tumor cells, the telomerase [85]. The tumoral cells express this enzyme that elongates the 3 ends of telomere [133]. Telomere shortening and telomerase activity have been detected in almost all human tumors but not in normal somatic tissues [133, 134], Zhang and cols, [85] showed that the telomerase inhibition by verbascoside may involve telomere-lenght regulation. 

Figure 11.4-1. Cellular senescence and immortalization. Telomere length is maintained by telomerase, and most human somatic cells have lower levels of telomerase. The cells are telomerase-negative and experience telomere shortening with each cell division. Shortened telomeres may start the cells to enter senescence at the Hayflick limit, or Ml. This proliferative checkpoint can be overcome by an inactivation of pRB/pl6 or p53, for example, by the use of SV40 or human papilloma virus oncoproteins. Snch cells continue to suffer telomere erosion and ultimately enter crisis, or M2, characterized by cell death. Quite a few surviving cells acquire stabilization of telomere length and unlimited proliferative potential, mostly due to activation of telomerase. (This figure is available in full color at ftp //ftp.wiley. com/public/sci tech med/pharmaceutical biotech/.)...

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