Telomerase and human tumorigenesis

Human cancer cells, unlike their normal counterparts, have shed the molecul ar restraints to limited cell growth and are immortal. Exactly how cancer c ells manage this at the molecular level is beginning to be understood. Huma n cells must overcome two barriers to cellular proliferation. The first bar rier referred to as senescence, minimally involves the p53 and Rb tumor-sup pressor pathways. Inactivation of these pathways results in some extension of lifespan. However inactivation of these pathways is insufficient for imm ortalization. As normal cells undergo repeated rounds of DNA replication, t heir telomeres shorten due to the inability of traditional DNA polymerases to completely replicate the end of the chromosomal DNA. This shortening con tinues until the cells reach a second proliferative block referred to as cr isis, which is characterized by chromosomal instability end-re-end fusions, and cell death. Stabilization of the telomeric DNA through either telomera se activation or the activation of the alternative mechanism of telomere ma intenance (ALT) is essential if the cells are to survive and proliferate in definitely. Conversely, loss of telomere stabilization by an already-immort alized cell results in loss of immortality and cell death. Together this in dicates that telomere maintenance is a critical component of immortality. I n this review we attempt to describe our current understanding of the role of telomere maintenance in senescence, crisis, and tumorigenesis.