Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia
Evidence that control of cellular proliferative potential may
be linked to telomere length, along with data indicating that
other factors may also be involved, will be reviewed. According
to the telomere hypothesis of senescence, the sequential loss
of telomeric repeat DNA that occurs during the replication of
normal somatic cells eventually dictates the onset of the permanently
nonreplicative state known as senescence. Many immortalized
cells express telomerase, a ribonucleoprotein enzyme that replaces
the telomeric DNA that would otherwise be lost due to replication.
However, some immortalized human cells may avoid telomeric shortening
without using telomerase. The mechanism involved is currently
unknown, but other eukaryotes are able to replace telomeric
DNA through (1) recombination and copy switching or (2) retrotransposition.
Human fibroblasts that lose p53 function proliferate a limited
number of times beyond the population-doubling level at which
their normal counterparts become senescent. Lack of functional
retinoblastoma (Rb) protein (or equivalent events, such as loss
of p16INK4 function, resulting in abrogation of Rb regulatory
activity) also permits a temporary extension of proliferative
potential. The p53 and pRb effects are additive, indicating
that they exert their control on proliferative potential separately.
The temporary life span extension associated with loss of p53
and/or Rb pathway function is accompanied by continued telomere
shortening. The proliferation arrest that eventually ensues
in p53-minus cells or in p53-minus/Rb-minus cells may be regarded
as terminal proliferation arrest states serving as a backup
to senescence. p53-minus/Rb-minus cells cannot proliferate further
unless they acquire the ability to prevent telomeric shortening.
Somatic cell hybridization and microcell-mediated chromosome
transfer experiments indicate that immortalization involves
the loss of function of other, as yet unidentified, genes; some
of these may normally repress telomerase expression in somatic
cells.
