A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cellsin Vitroandin Vivo

Mata, John E.; Joshi, S. K.; Palen, Brian; Pirruccello, Samuel J.; Jackson, John D.; Elias, Nadia; Page, Todd J.; Medlin, Kristin L.; Iversen, Patrick L.

doi:10.1006/taap.1997.8103

Cited by 73 publications

(43 citation statements)

References 26 publications

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“…Under these conditions, the cell growth rate was compared between vector-and hTERT-transfected cells with or without inhibitor treatment and the results were shown in Figure 1e. As expected, the cell proliferation was distinctly slowed down when telomerase activity was inhibited in pCI-HLE and pCIhTERT-HLE cells (Figure 1e), a result similar to that observed in Burkitt's lymphoma cells (Mata et al, 1997).…”

supporting

confidence: 86%

“…To con®rm that the observed acceleration of cell growth is derived from overexpression of hTERT in HLE, we treated both vector-and hTERT-transfected HLE with a telomerase inhibitor, a hexameric oligonucleotide, 5'-d(TTAGGG)-3' or a control oligonucleotide, 5'-d(TGTGAG)-3'. Previous studies have established that the 5'-d(TTAGGG)-3' oligonucleotide is e ective in inhibiting telomerase activity in several di erent types of cells in culture (Morin, 1989;Mata et al, 1997;Fu et al, 1999). As shown in Figure 1d, while 20 mM of 5'-d(TTAGGG)-3' was able to substantially inhibit telomerase activity in both pCI-HLE and pCIhTERT-HLE cells, the control oligonucleotide had little e ect.…”

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confidence: 80%

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Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway

et al. 2002

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Telomerase is a specialized reverse transcriptase that extends telomeres of eukaryotic chromosomes. The catalytic core of human telomerase is composed of an RNA template known as hTER (human telomerase RNA) and a protein subunit named hTERT (human telomerase reverse transcriptase). We have been studying other functions of the telomerase besides its major role in telomere maintenance. In our previous work, we have demonstrated that the hTERT can functionally interact with a rabbit TER to regulate expression of other genes and also attenuate the induced apoptosis. Here we report that overexpression of hTERT in a human lens epithelial cell line accelerates growth of the transfected lens epithelial cells. Associated with the acceleration of cell growth, expression of p53, p21 and GCIP (Grap2 cyclin-D interacting protein) is downregulated in the hTERTtransfected cells. With the downregulation of p21 and GCIP, the retinoblastoma protein (RB) is completely hyperphosphorylated in the hTERT-transfected cells. As expected, in the presence of RB hyperphosphorylation, the E2F transactivity is upregulated. Inhibition of telomerase activity abolishes the observed growth acceleration and also the related molecular changes. Furthermore, expression of hTERT in telomerasenegative human lens epithelial cells derived from primary cultures also accelerates growth of the transfected cells. Taken together, our results suggest that hTERT, when overexpressed in human lens epithelial cells, accelerates cell growth rate through regulation of RB/E2F pathway and possibly other genes.

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confidence: 86%

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confidence: 80%

Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway

et al. 2002

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“…(TTAGGG) that have been shown to suppress telomerase activity (15,23). Both agents effectively suppressed telomerase activity in human VSMC in the range of 0.1 to 1 M (data not shown) and significantly shortened the cell life span of hypoxic cultures (Fig.…”

Section: Fig 2 Hypoxia Induces Telomerase Activity (A)mentioning

confidence: 87%

Hypoxia Extends the Life Span of Vascular Smooth Muscle Cells through Telomerase Activation

Minamino

Mitsialis

Kourembanas

2001

Molecular and Cellular Biology

165

120

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Chronic hypoxia induces smooth muscle cell proliferation and vessel wall remodeling in the vasculature of the lung. One well-characterized component of the hypoxic response is transcriptional activation of genes encoding vascular smooth muscle cell (VSMC) mitogens. We report here that chronic hypoxia can also prolong the growth of human VSMC by inducing telomerase activity and telomere stabilization. We demonstrate that hypoxia induced phosphorylation of the telomerase catalytic component (TERT) and sustained high levels of TERT protein expression in VSMC compared to normoxia. Furthermore, inhibition of telomerase shortened cell life span in hypoxic cultures, whereas constitutive expression of TERT extended the life span of cells under normoxic conditions. Our data indicate that hypoxic induction of telomerase activity could be involved in long-term growth of VSMC and may thus contribute to human vascular disorders.Hypoxia is an important regulator of physiologic processes, including erythropoiesis, angiogenesis, and glycolysis (6). In the vasculature, chronic hypoxia has been shown to cause proliferation of vascular smooth muscle cells (VSMC), leading to vessel wall remodeling, a key pathophysiologic component of pulmonary hypertension (11). The mechanisms by which hypoxia regulates VSMC growth include direct cell cycle-specific effects, as well as indirect effects, via the regulation of VSMC mitogen production by endothelial cells (10). Hypoxia triggers a cellular adaptive response that is primarily mediated by the transcription factor hypoxia-inducible factor 1 (HIF-1) (20). Expression of HIF-1 target genes serves to maintain cellular homeostasis. Transcriptional activation of hypoxia-responsive genes represents one major component of the vascular cell hypoxic response; however, the mechanisms regulating longterm VSMC proliferation in the vessel wall under chronic hypoxia remain to be elucidated.Telomere integrity is essential for chromosome stability (5) and therefore plays a crucial role in long-term cell proliferation. Telomere length is maintained by telomerase, a ribonucleoprotein that uses its associated RNA moiety as a template to add telomeric repeats onto chromosome ends. High levels of telomerase activity are readily detected in cancer cells but not in most normal somatic cells, indicating that telomerase function is required for tumor growth (9). Recent studies indicate that telomerase activity is also present in highly proliferative somatic cell types, such as activated lymphocytes (7). Moreover, in later generations of mice lacking telomerase RNA, there is decreased cell proliferation in highly proliferative organs (12), suggesting that telomerase activity may also be required for proliferation and long-term viability in these cells.The mammalian telomerase RNA component (TERC) has been identified, and its expression was shown to correlate with cell proliferation as well as with telomerase activity in cancer cells (3). Recently, two protein components have been isolated, the mammalian homologue o...

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“…Since most normal cells lack this enzyme, it is an appealing target, in that, inhibition could cause minimal damage elsewhere in the patient. Previously, the ability of the phosphorothioate TAG oligomers to specifically inhibit telomerase activity (Mata et al, 1997) and permeate the skin, using iontophoresis (Brand and Iversen, 1996;Brand et al, 1998a) has been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Transdermal delivery of phosphorodiamidate Morpholino oligomers across hairless mouse skin

Pannier

Arora

Iversen

et al. 2004

International Journal of Pharmaceutics

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A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cellsin Vitroandin Vivo

Cited by 73 publications

References 26 publications

Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway

Human telomerase accelerates growth of lens epithelial cells through regulation of the genes mediating RB/E2F pathway

Hypoxia Extends the Life Span of Vascular Smooth Muscle Cells through Telomerase Activation

Transdermal delivery of phosphorodiamidate Morpholino oligomers across hairless mouse skin

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