[Telomerase, elixir of life for human cells?].
Telomeres are specialized structures at the end of eukaryotic chromosomes that in vertebrates constain hundreds to thousands of tandem repeats of the sequence TTAGGG. In most human somatic cells, telomeres shorten with each cell division, eventually triggering an irreversible arrest of proliferation called cellular senescence. These observations have led to a model in which telomere length reflects the mitotic history of somatic cells. Further support for this hypothesis has come from the discovery of telomerase, a unique reverse transcriptase ribonucleoprotein that has the ability to extend 3' end of telomeres. In fibroblasts, senescence is induced by telomere attrition and depends on p53 and pRb pathways triggered by one or a few critically short telomeres. Previous studies have shown that the replicative life span of various primary human cells can be prolonged by transduction of the telomerase reverse transcriptase (hTERT) gene. The hTERT expressing cells proliferate indefinitely, without undergoing any changes associated with transformation to malignancy. Rapid progress has been made towards the goal of using tumor-specific cytolytic CD8+ T lymphocytes for the immunotherapy of cancer. These cells can be expanded in vitro and, in principle, could be used for adoptive immunotherapy. One of the major problems that remains to be solved is the finite life span of normal human T lymphocytes. In an attempt to overcome this barrier three groups have introduced hTERT cDNA into human T lymphocytes and monitored its effect on their life span. In two of these studies, hTERT significantly extended the replicative life span of CD8+ T clones, whereas this was not the case in the third study using bulk T lymphocytes. Possible explanations for these discordant results are that better growth conditions avoided culture-induced stress in the study with clones, or that clones had undergone alterations leading, for example, to the inactivation of the pRb pathway during their derivation.
Rufer
Nathalie
N
Laboratoire de Biologie des Lymphocytes, Institut Suisse de Recherche Expérimentale sur le Cancer (ISREC), 155, chemin des Boveresses, 1066 Epalinges, Suisse. nathalie.rufer@isrec.unil.ch
Nabholz
Markus
M
D000818:Animals; D002455:Cell Division; D002470:Cell Survival; D002875:Chromosomes; D004268:DNA-Binding Proteins; D005057:Eukaryotic Cells / Q000502:physiology; D006801:Humans; D007107:Immune System / Q000502:physiology; D007167:Immunotherapy; D007239:Infections; D008214:Lymphocytes / Q000502:physiology*; D019098:Telomerase / Q000235:genetics / Q000494:pharmacology*; D018911:Trinucleotide Repeats
D004268:DNA-Binding Proteins; D019098:Telomerase