Cell proliferation, carcinogenesis and diverse mechanisms of telomerase regulation

Abstract

Replication of linear genomes is incomplete and leaves terminal gaps. Solutions to this 'end replication' problem can be traced back to the prebiotic RNA world: 'fossils' of the presumptive archetypes of telomere structure and of the telomerase enzyme are retained in the terminal structures of some RNA viruses. Telomerase expression in mammals is ubiquitous in embryonic tissues but downregulated in somatic tissues of adults. Exceptions are regenerative tissues and, notably, tumor cells. Telomerase activation is controlled by cellular proliferation, and it is an early step in the development of many tumors. In contrast to mammals, indeterminately growing multicellular organisms, such as fish and crustaceae, maintain telomerase competence in all somatic tissues. In human tumor diagnostics, detection of proliferation markers with monoclonal antibodies is well established, and in this review, the significance of additional telomerase assays is evaluated. Telomerase inhibitors are attractive goals for application in tumor therapy, and telomerase knockout mice have proven that telomere erosion limits the lifespan of cells in vivo. In contrast, telomerase stimulation can be used to expand the potential of cellular proliferation in vitro, with possible applications for transplantation of in vitro expanded human cells, for immortalizing primary human cells as improved tissue models and for the isolation of otherwise intractable products, such as genuine human monoclonal antibodies.

Telomerase expression in B-cell chronic lymphocytic leukemia predicts survival and delineates subgroups of patients with the same igVH mutation status and different outcome

“…32,33 The selective pressure of hTERT activation by telomere erosion to a critical stage is a usual hallmark in tumorigenesis. 34 Finding that B-CLL cases with short telomeres had more telomerase activity than those with longer telomeres 12 supports this concept. Levels of both hTERT-AT and hTERT-FL transcripts were significantly higher in patients with an unmutated rather than mutated IgVH profile, but there was no strong association between percentages of IgVH mutations and hTERT mRNA levels.…”

Long lifespan in worms with long telomeric DNA

“…4D denotes a double-stranded form. Chromosomes in linear forms are doomed to be shortened by the nature of DNA replication and, unless there is a specific protection mechanism, limit the number of cell divisions 1,2 . The telomere hypothesis explains how telomere length limits cellular senescence 3 .…”

Nestin expression and clonal analysis of islet-derived epithelial monolayers: insight into nestin-expressing cell heterogeneity and differentiation potential

“…The observation of nestin and telomerase co-localization is of particular interest. Telomerase is a specific reverse transcriptase that synthesizes new telomeric repeats on the chromosome end to compensate for telomeric loss due to an 'end-replication-problem', providing the basis for an unlimited proliferative capacity (Krupp 2000). It is present in normal immortal human embryonic stem cells (Amit et al 2000) and in germ line cells, both of which proliferate continuously without signs of aberrant growth control.…”