Radiobiology for the Radiologist by Eric J. Hall & Amato J. Giaccia

Author:Eric J. Hall & Amato J. Giaccia
Language: eng
Format: mobi
ISBN: 9781496335418
Publisher: Wolters Kluwer Health
Published: 2018-04-15T16:00:00+00:00

FIGURE 18.15 In vitro senescence has been classically defined in fibroblasts that go through a defined number of generations before they stop proliferating. This permanent arrest has been termed senescence. It is characterized biochemically by increased SA-β-galactosidase activity in the lysosomes and shortened telomeres (telomere restriction fragments [TRF]). Primary cells on the way to immortalization must overcome the crisis of shortened telomeres by reactivating telomerase and losing the p53 and pRb (p16 loss) control over the cell cycle and apoptosis to survive.

Mammalian telomeres consist of long arrays of the repeat sequence TTAGGG that range in length anywhere from 1.5 to 150 kb. Each time a normal somatic cell divides, the terminal end of the telomere is lost; successive divisions lead to progressive shortening, and after 40 to 60 divisions, vital DNA sequences are lost. At this point, the cell cannot divide further and undergoes senescence. Telomere length has been described as the “molecular clock” because it shortens with age in somatic tissue cells during adult life. Stem cells in self-renewing tissues, and cancer cells in particular, avoid this process of aging by activating the enzyme telomerase. Telomerase is a reverse transcriptase that polymerizes TTAGGG repeats to offset the degradation of chromosome ends that occurs with successive cell divisions; in this way, the cell becomes immortal. Telomere shortening inhibits tumor expansion when the p53 tumor suppressor gene is intact. Although it has not been proven, telomeres seem to engage the p53 pathway by inducing a damage response signaled through the ATM pathway (see Chapter 2). Studies have shown that telomere shortening leads to senescence and tumor suppression in cells with an intact p53 pathway. Surprisingly, telomere shortening accelerates tumorigenesis in cells that were deficient in p53 activity. The ability of shortened telomeres to accelerate tumorigenesis in p53-deficient cells results from increased chromosomal instability and rearrangements and gene amplification.

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