c-Myc-mediated regulation of telomerase activity is disabled in immortalized cells

Myc overexpression is a hallmark of human cancer and promotes transformatio n by facilitating immortalization. This function has been linked to the abi lity of c-Myc to induce the expression of the catalytic subunit of telomera se, telomerase reverse transcriptase (TERT), as ectopic expression of TERT immortalizes some primary human cell types. c-Myc up-regulates telomerase a ctivity in primary mouse embryonic fibroblasts (MEFs) and myeloid cells. Pa radoxically, Myc overexpression also triggers the ARF-p53 apoptotic program , which is activated when MEFs undergo replicative crises following culture ex vivo. The rare immortal variants that arise from these cultures general ly suffer mutations in p53 or delete Ink4a/ARF, and Myc greatly increases t he frequency of these events. Alternative reading frame (ARF)- and p53-null MEFs have increased telomerase activity, as do variant immortal clones tha t bypass replicative crisis. Similarly, immortal murine NIH-3T3 fibroblasts and myeloid 32D.3 and FDC-P1.2 cells do not express ARF and have robust te lomerase activity. However Myc overexpression in these immortal cells resul ts ever, I in remarkably discordant regulation of TERT and telomerase activ ity. Furthermore, in MEFs and 32D.3 cells TERT expression and telomerase ac tivity are regulated independently of endogenous c-Myc. Thus, the regulatio n of TERT and telomerase activity is complex and is also regulated by facto rs other than Myc, ARF, or p53.