Telomerase activity and cellular immortalization

Normal human cells undergo a limited number of divisions and eventually undergo senescence. This is accompanied by several changes, including increases in inhibitors of cyclin-dependent kinases and shortening of telomeres. Expression of the catalytic component of telomerase, hTERT, significantly extends the lifespan of human fibroblasts but is not sufficient for the immortalization of human keratinocyte or breast epithelial cells. However, inactivation of the Rb/p16ink4a pathway, or down-regulation of p16ink4a expression in combination with hTERT, is capable of immortalizing human epithelial cells efficiently. Elimination of p53, and of the DNA-damage-induced checkpoint is not required for immortalization, nor is a consistent loss of p19ARF.