The Wilms' Tumor 1 Tumor Suppressor Gene Represses Transcription of the Human Telomerase Reverse Transcriptase Gene

Oh, Sangtaek; Song, Young Ho; Yim, Joon-Hyuk; Kim, Tae Kook

doi:10.1074/jbc.274.52.37473

Cited by 127 publications

(99 citation statements)

References 32 publications

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“…Other factors may also be involved in hTERT repression. For example, it has been reported that transcription factor E2F1, tumor suppressors Menin and Wilms' tumor 1 (WT1), and the TGF-␤ signaling pathway all mediated hTERT transcriptional repression in various cell types (Oh et al, 1999;Crowe et al, 2001;Lin and Elledge, 2003). The roles of these factors in hTERT repression during development remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells

Wang

Zhu

2007

MBoC

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The human telomerase reverse transcriptase hTERT is highly expressed in undifferentiated embryonic cells and silenced in the majority of somatic cells. To investigate the mechanisms of hTERT silencing, we have developed a novel reporter using a bacterial artificial chromosome (BAC) that contained the entire hTERT gene and its neighboring loci, hCRR9 and hXtrp2. Firefly and Renilla luciferases were used to monitor transcription from the hTERT and hCRR9 promoters, respectively. In mouse embryonic stem cells stably integrated with the BAC reporter, both hTERT and hCRR9 promoters were highly expressed. Upon differentiation into embryoid bodies and further into mineral-producing osteogenic cells, the hTERT promoter activity decreased progressively, whereas the hCRR9 promoter remained highly active, both resembling their endogenous counterparts. In fully differentiated cells, the hTERT promoter was completely silenced and adopted a chromatin structure that was similar to its native counterpart in human cells. Inhibition of histone deacetylases led to the opening of the hTERT promoter and partially relieved repression, suggesting that histone deacetylation was necessary but not sufficient for hTERT silencing. Thus, our result demonstrated that developmental silencing of the human TERT locus could be recapitulated in a chromosomal position-independent manner during the differentiation of mouse embryonic stem cells. INTRODUCTIONThe differentiation and lineage commitment of stem cells are accompanied and determined by chromatin remodeling and establishment of epigenetic marks (Szutorisz and Dillon, 2005). The process of differentiation involves switching on or off genes that are expressed in specific types of cells and at specific times. This programming of gene transcription occurs in the context of their native chromatin environment and is often stably maintained throughout the life span of an organism. Many genes essential for proper development of the embryo have been discovered and most of them encode proteins that regulate transcription (Arney and Fisher, 2004;Chambers and Smith, 2004). However, the dynamic interactions between these proteins and chromatin are still areas of intensive investigation. Detailed studies of gene transcription regulatory mechanisms during cell differentiation are essential not only for understanding the fundamental mechanisms of development and differentiation, but also for harnessing the differentiation and proliferation capacity that make stem cells invaluable for regenerative medicine.Telomerase, an enzyme synthesizing TTAGGG telomere repeats, is pertinent to self-renewal potential of stem cells and is required for long-term cellular proliferation and survival (Morrison et al., 1996;Lee et al., 1998). Telomerase is tightly regulated throughout development (Kim et al., 1994;Prowse and Greider, 1995). In early embryonic tissues and stem cells, telomerase is highly expressed and telomeres are stably maintained (Wright et al., 1996;Sharpless and DePinho, 2004). Although telomerase is detec...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells

Wang

Zhu

2007

MBoC

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“…The mechanisms by which the hTERT core promoter works so differentially in tumors and normal cells are still unclear. However, it has been reported that c-Myc, 29,[53][54][55][56][57] Sp1 57 and estrogen 58,59 activated hTERT promoter, but p53, 60 WT-1 61 and Mad1 62 were important factors for the Figure 10 Ad5/3hTERTE1 suppressed tumor growth in vivo. Intact SBC5 cells (1 Â 10 7 ) were injected s.c. into nude mice.…”

Section: Discussionmentioning

confidence: 99%

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment

et al. 2005

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Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoterbased CRAds may be a potentially effective strategy for cancer treatment.

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“…However, multiple control elements can be found throughout the promoter region and may lead to the characterization of the factors involved. For instance, estrogen, 35,36 c-Myc 37-42 and Sp1 43 have been found to activate transcription of the hTERT gene, whereas p53, 44 WT-1 45 and Mad1 31 down-regulate its transcription. Of particular interest, is the finding that the differential activities of the hTERT promoter in normal and tumor lines could be attributed to the abundance of the c-Myc oncoprotein.…”

Section: Discussionmentioning

confidence: 99%

The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters

et al. 2001

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The Wilms' Tumor 1 Tumor Suppressor Gene Represses Transcription of the Human Telomerase Reverse Transcriptase Gene

Cited by 127 publications

References 32 publications

Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells

Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment

The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters

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