3.3. RELATIONSHIP BETWEEN TELOMERE SHORTENING AND CELLULAR SENESCENCE
In contrast to established tumor cell lines, which can divide indefinitely (are "immortal"). Normal diploid human cells have a limited capacity to proliferate (are "mortal"). In general, fibroblasts cultured from a fetus divide more times in culture than those from a child, which in turn divide more times than those from an adult. The length of the telomeres decreases both as a function of donor age and correlates with the number of times a cell has divided. There appear to be two mechanisms responsible for the proliferative arrest of normal cells (8-10). The first Ml (Mortality stage 1), occurs when there are still at least several thousand base pairs of telomeric sequences left at the end of most of the chromosomes.
It is possible that Ml may be induced by the activation of genes located in the immediately subtelomeric region of the chromosomes, by liberation of transcription factors bound or sequestered by telomeres (8), or by a DNA damage signal produced by one or a few of the 92 telomeres that have particularly short telomeres (7). The Ml mechanism causes a growth arrest mediated by the cell cycle regulatory genes p53/p21 and genes in the pRb/pl6 pathway (15-17). If the actions of p53/p21 and pRB/pl6 are blocked, either by mutation or by binding to oncoproteins such as SV40 large T-antigen or the E6/E7 proteins from high risk strains of papilloma viruses, then the cells can continue to divide and telomeres proceed to shorten until a second independent cellular mechanism, M2 (Mortality stage 2) is induced (27-29).
M2 probably represents the physiological result of critically short telomeres when cells are no longer able to protect the ends of the chromosomes, so that end-degradation and end-to-end fusions occur, resulting in genomic instability and inhibition of cell growth or cell death. In cultured cells at M2, a focus of immortal cells occasionally arises, and in most cases these cells have upregulated or reactivated the expression of the enzyme telomerase, which is able to repair and maintain the telomeres.