Cellular senescence mechanisms independent of telomere shortening and telomerase: Other barriers to cell immortalization and carcinogenesis

Normal human somatic cells stop dividing after a limited number of cell divisions through the process termed "cellular senescence," which may function as a tumor-suppressive mechanism. Although the regulation of telomerase activity and telomere length plays an important role in cellular senescence and immortalization in human cells, recent findings from the telomerase introduction experiment, chromosome transfer experiment and studies on the inducers of premature senescence suggest that there are multiple mechanisms to induce cellular senescence, some of which are independent of telomerase and telomere regulation. Inactivation of the function of cell cycle regulatory p16(INK4A)/Rb pathway is a key event in immortalization. In rodents, which have long telomeres and telomerase activity, telomere shortening is not correlated with cellular senescence. These models may be useful to elucidate telomere-independent pathways in human cells. Studies in this field will clarify the barriers to human cell immortalization and carcinogenesis.