Genes involved in the control of cellular proliferative potential.

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.