Myc activates telomerase

Abstract

Telomere maintenance has been proposed as an essential prerequisite to human tumor development. The telomerase enzyme is itself a marker for tumor cells, but the genetic alterations that activate the enzyme during neoplastic transformation have remained a mystery. Here, we show that Myc induces telomerase in both normal human mammary epithelial cells (HMECs) and normal human diploid fibroblasts. Myc increases expression of hEST2 (hTRT/TP2), the limiting subunit of telomerase, and both Myc and hEST2 can extend the life span of HMECs. The ability of Myc to activate telomerase may contribute to its ability to promote tumor formation.

Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation

“…cyclin D1 and E2F-1) or p53 (e.g. Mdm2) pathways are not capable of inducing telomerase activity (Wang et al, 1998 and our data not shown), suggesting that cMyc may play a critical role in regulation of TERT expression and hence telomerase activity. Here, we observe that c-Myc acts as a potent activator of telomerase activity through the rapid upregulation of TERT gene expression.…”

“…The prominence of TERT in telomere homeostasis and the pro®le of TERT gene expression in normal and neoplastic settings prompted us to determine whether various cellular growth control and transcriptional factors regulate TERT gene expression and/or telomerase activity in primary human lung ®broblasts. Recent evidence indicates that expression of TERT and telomerase activity can be induced by the E6 oncoprotein or by c-Myc (Wang et al, 1998). Other oncogenes (e.g.…”

“…Employing this cell culture system, 4-OHT treatment of MycER-transduced IMR90 cultures resulted in the marked and sustained activation of telomerase to a level at or above that detected in lysates derived from an equivalent number of telomerase-positive 293T tumor cells as assayed by the sensitive TRAP assay ( Notably, enforced expression of oncogenes such as H-Ras, and cellular modulators of the Rb and p53 pathways (E7, cyclin D1, Mdm2, dominant-negative p53) were not capable of in¯uencing telomerase activity in IMR90 cells (Wang et al, 1998 and our data not shown). These observations suggested that Myc may play a prominent and direct role in the regulation of hTERT gene expression.…”

“…Expression of hTERT in BJ ®broblasts or retinal pigment epithelial cells is known to extend lifespan of these cells beyond the Hay¯ick limit (Bodnar et al, 1998). Similarly, expression of c-Myc in IMR90 ®broblasts and human mammary epithelial cells extends the lifespan of these cells with a concomitant increase in telomerase activity (Wang et al, 1998). Therefore, the ability of Myc to stimulate expression of hTERT directly could account in part for the immortalizing function of Myc and the concomitant increases in hTERT expression.…”

“…These observations, together with highly similar expression pro®les for mTERT and c-myc during mouse erythroleukemia (MEL) cell di erentiation and mitogen-stimulated lymphocyte proliferation (Greenberg et al, 1998;Lachman and Skoultchi, 1984;Reed et al, 1986), imply a potential link between increased Myc transactivation activity and up-regulation of TERT gene expression in normal proliferating and transformed cells. Indeed, recent evidence has shown that enforced expression of c-Myc in normal human ®broblasts or normal human mammary epithelial cells leads to increased expression of hTERT (Wang et al, 1998). However, to date it remains unclear as to whether c-Myc acts directly to upregulate transcription of the hTERT gene and whether this TERT gene activation by Myc represents a critical functional aspect of Myc immortalization activity.…”