Klin Onkol 2001; 14(5): 145-153.
Summary: Cellular immortalization represents a multistep process, during which cells acquire indefinite proliferation potential. The immortalized phenotype is typical to tumour cells and tumour-derived cell lines, whereas normal somatic cells, primary cultures and finite cell lines enter after a period of active proliferation into a state of proliferation arrest termed senescence. The senescence is characterized by activation of tumour suppressor proteins p53 and p16INK4a, inhibition of cyclindependent kinases activation, by pRb hypophosphorylation and constant inactivation of E2F transcription factors. Consequently, genes encoding for proteins, which are crucial for entry into S-phase, are not expressed. The point of senescence seems to be determined by two parallel processes – a gradual shortening of telomeres upon each cell division and a progressive demethylation of the genome. Mutagenesis, infection by DNA-tumour viruses or transfection with their oncogenes entail a bypass of senescence and allow for additional proliferation beyond the senescence point. Shortening of telomeres continues during this prolonged proliferation period, however, and proliferation terminates in culture crisis, which is typified by extensive cell death. A part of the cellular population might, nevertheless, activate a telomere maintenance mechanism (most frequently telomerase) and those cells spontaneously recover from crisis and become immortal. Immortality represents a recessive phenotype, which is conditioned by a gradual assembly of mutation hits targeting both copies of senescenceor crisismediating genes. Besides this replicative senescence, essentially the same phenotype could be induced prematurely (i.e. before passing the number of cell divisions, which would trigger the replicative senescence), e.g. by dominant gain-of-function activating mutations in the ras-oncogene on an otherwise normal genetic background. This premature senescence, as well as the replicative senescence for its own sake, could be this viewed as natural tumour suppressor barriers. Activated ras is able to bypass this proliferation block by cooperating with additional cellular oncogene –myc. However, the activation of myc leads in addition to the bypass of crisis, by means of activating transcription of the gene encoding the telomerase catalytic subunit, as well as to multiple additional consequences along the tumour progression pathway. The telomerase is often regarded as a promising target of anti-tumour therapy, its regulated expression on the other side represents a possibly important point in cell-based therapeutic applications.
