Mechanisms of escaping cellular senescence

Jerry W. Shay, Woodring E. Wright

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The two‐stage model of cellular senescence, M1 (mortality stage 1) and M2 (mortality stage 2), represents independent mechanisms limiting the proliferative capacity of normal somatic cells. The cellular proteins p53 and either pRB or an RB‐like activity appear to be important in the inhibition of cell proliferation that occurs when the M1 mechanism is activated. Because telomeres (the ends of chromosomes) shorten progressively with each cell division in normal somatic cells, it has been proposed that telomere attrition is the molecular measure (clock) of the proliferative potential remaining in cells. However, the M1 mechanism is activated when there are several kilobases of telomeric repeats left; thus, presently, it is not understood how or if telomere shortening controls the onset of the M1 mechanism. In the presence of viral oncogenes or somatic mutations that block cellular senescence, cells divide beyond M1 (extension of life span), and telomere erosion continues. This process persists until a second independent mechanism, M2, is activated, again resulting in inhibition of cell proliferation. The M2 mechanism may result from terminal telomere shortening, when there are so few telomeric repeats remaining that cells either stop dividing or die. In tumor‐derived cell lines, telomeres do not continue to shorten and are maintained by the ribonucleoprotein enzyme telomerase. In almost all normal human somatic cells, telomerase activity is repressed. A hypothesis that is gaining momentum is that a rare cell escapes M2 by inactivating the pathway repressing telomerase. The reactivation of telomerase may be a necessary event for the sustained growth of most human tumors. © 1995 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)284-289
Number of pages6
JournalRadiation Oncology Investigations
Volume3
Issue number6
DOIs
StatePublished - 1995

Keywords

  • aging
  • immortalization
  • p53
  • pRB
  • telomerase
  • telomeres

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology
  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging

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