hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization

Abstract

Telomerase, the ribonucleoprotein enzyme that elongates telomeres, is repressed in normal human somatic cells but is reactivated during tumor progression. We report the cloning of a human gene, hEST2, that shares significant sequence similarity with the telomerase catalytic subunit genes of lower eukaryotes. hEST2 is expressed at high levels in primary tumors, cancer cell lines, and telomerase-positive tissues but is undetectable in telomerase-negative cell lines and differentiated telomerase-negative tissues. Moreover, the message is up-regulated concomitant with the activation of telomerase during the immortalization of cultured cells and down-regulated during in vitro cellular differentiation. Taken together, these observations suggest that the induction of hEST2 mRNA expression is required for the telomerase activation that occurs during cellular immortalization and tumor progression.

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

“…53 Despite the general similarity in promoter sequence, there are some important differences in mTERT and hTERT regulation. Unlike humans, in which the expression of hTERT is limited to a small number of normal tissues, 25 mTERT expression is widely expressed at low levels in many adult tissues. 52 Despite the difference in expression pattern, adenoviral vectors using the hTERT promoter to drive LacZ or HSV-thymidine kinase genes had undetectable transgene expression in the livers of mice, 28,30,33 suggesting that activity of the hTERT promoter is low in normal mouse liver.…”

“…4 The hTERT gene has been previously shown to be selectively expressed in the majority of human cancers. [23][24][25][26][27][28] Furthermore, the hTERT promoter has been shown to confer tumor-selective expression of the linked gene in plasmids and Ad constructs. [28][29][30][31][32][33] Oncolytic adenoviruses utilizing the hTERT promoter to control Ad early region genes have also been previously described.…”

Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation

“…Telomeres consist of lengthy G-rich simple repeat sequences that are synthesized de novo by a specialized reverse transcriptase known as telomerase (Greider and Blackburn, 1985;Yu et al, 1990;Singer and Gottschling, 1994). The telomerase core enzyme consists of an RNA component and a polypeptide that bears classical structural motifs and functional activities of a reverse transcriptase Nakamura et al, 1997Nakamura et al, , 1998Meyerson et al, 1997;Harrington et al, 1997;Kilian et al, 1997;. As conventional DNA-dependent DNA polymerases fail to fully replicate the ends of chromosomes, telomerase has evolved to serve as the primary means by which eukaryotic cells maintain telomere length with each cell division cycle.…”

“…The human telomerase reverse transcriptase protein (previously hTRT, now known as hTERT) has recently been cloned by Nakamura et al (1997) and by others under di erent names (hEST2, hTLP2, hTCS1, hTRT) (Meyerson et al, 1997;Harrington et al, 1997;Kilian et al, 1997;Nakayama et al, 1998). These studies, using primary and immortalized human cell lines, have established that an additional level of telomerase activity regulation is achieved through mechanisms governing expression of hTERT Nakamura et al, 1997Nakamura et al, , 1998Meyerson et al, 1997;Harrington et al, 1997;Kilian et al, 1997). In this study, we have isolated and characterized the mouse ortholog of hTERT with the goals of understanding the regulation of telomerase activity in normal and neoplastic processes in the mouse, providing insights into the immortalization behavior of mouse and human cells, and characterizing the catalytic activities of the mouse protein.…”

Induction of telomerase activity in v-myc-transformed avian cells

“…In human cells, for instance, an immortalizing oncogene like SV40 large T antigen extends the replicative potential of infected ®broblasts past their Hay¯ick limit (Hay¯ick and Moorhead, 1961). Telomerase is only expressed in post-crisis cells (Meyerson et al, 1997), however, and the emergence of immortal clones is a rare event occurring with an extremely low probability (reviewed in Vojta and Barrett, 1995). Activation of telomerase in isolated Figure 2 Induction of telomerase activity by MC29 and MC29 td10H in quail myoblasts.…”