Telomerase overexpression in K562 leukemia cells protects against apoptosis by serum deprivation and double-stranded DNA break inducing agents, but not against DNA synthesis inhibitors

Akiyama, Masaharu; Yamada, Osamu; Kanda, Naotoshi; Akita, S; Kawano, Takeshi; Ohno, Tsuneya; Mizoguchi, Hideaki; Eto, Yoshikatsu; Anderson, Kenneth C.; Yamada, Hisashi

doi:10.1016/s0304-3835(01)00838-2

Cited by 65 publications

(44 citation statements)

References 27 publications

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“…Up-regulation of TA may represent a physiologic protective mechanism against DNA damage, contributing to DNA repair by chromosomal healing (48) and enhanced survival. This hypothesis is supported by studies such as of Akiyama et al, showing that overexpression of telomerase protects from apoptosis triggered by doublestranded DNA damage (49).…”

Section: Discussionmentioning

confidence: 61%

Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

Ram

Uziel²,

Eldan³

et al. 2009

Clinical Cancer Research

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Purpose:Telomerase is considered currently as a hallmark of cancer, and its inhibition is expected to become an important anticancer modality. In contrast to abundant data concerning the effect of cytotoxic drugs on telomerase activity (TA), there is scant information on the effect of radiation on telomerase.The mechanism of telomerase regulation by irradiation has never been evaluated in detail. In the present study, we investigated the effect of radiation onTA and its regulation in cancer cells. Experimental Design:The effect of various radiation doses onTA in several malignant and nonmalignant cell lines was evaluated. All malignant cells exhibited similar telomerase response to radiation and its regulation was assessed at transcriptional and post-translational levels in K562 cells. Next step was the evaluation of the upstream signaling pathways leading to changes inTA using kinetics and specific inhibitors. Results: Radiation up-regulated TA in dose-dependent manner only in cancer cells. Telomerase was activated by phosphorylation by Akt and by cytoplasmic-nuclear shift. Transcriptional processes were not involved inTA. This telomerase regulation is mediated by Ras/phosphatidylinositol 3-kinase/Akt pathway. The canonical membrane effectors of irradiation (epidermal growth factor receptor, insulin-like growth factor-I receptor, and Ca 2+ influx) were not involved in this process. Conclusions: Radiation up-regulates telomerase activity specifically in cancer cells. This study adds to accumulating evidence pointing to post-translational level as important mode of telomerase regulation. Telomerase activation due to radiation may be detrimental in treatment of cancer. Data described in this study may add to future interventions aiming at inhibition of telomerase activation during irradiation.

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Section: Discussionmentioning

confidence: 61%

Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

Ram

Uziel²,

Eldan³

et al. 2009

Clinical Cancer Research

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“…Overexpression of human TERT (hTERT) in various cell lines resulted in resistance to several forms of apoptosis and in extended cellular life-span Akiyama et al, 2002;Gorbunova et al, 2002;Luiten et al, 2003). By contrast, ablation of telomerase activity by antisense approaches or by expression of the dominant-negative hTERT resulted in enhanced sensitivity to cell death and consequently, growth inhibition (Fu et al, 1999;Misawa et al, 2002;Yuan and Mei, 2002;Nakajima et al, 2003;Teng et al, 2003;Liu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis

Lee

Hande

Sabapathy

2005

Journal of Cell Science

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“…Moreover, we and others have found that EGF stimulates contraction of smooth muscle (12,13). Importantly, we identified that EGF has differential intracellular signaling mechanisms in longitudinal and circular gastric smooth muscle (14). In cultured VSMCs, several studies have shown that the direct or indirect activation of EGF receptor stimulates proliferation of cultured VSMCs (15)(16)(17).…”

mentioning

confidence: 97%

Epidermal Growth Factor Induction of Phenotype-dependent Cell Cycle Arrest in Vascular Smooth Muscle Cells Is through the Mitogen-activated Protein Kinase Pathway

Gui

Zheng

2003

Journal of Biological Chemistry

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The heterogeneity of vascular smooth muscle cells is well established in tissue culture, but their differential responses to growth factors are not completely defined. We wished to identify effects of epidermal growth factor (EGF) on vascular smooth muscle cells in distinct phenotypes, such as spindle and epithelioid. We found that the EGF receptors were abundant in epithelioid cells but not spindle cells. EGF treatment inhibited serumindependent DNA synthesis, which was absent in spindle cells, of epithelioid cells. Additionally, using a pulsechase assay, we found that bromodeoxyuridine-labeled cells failed to re-enter the S phase in the presence of EGF. These EGF effects were abolished by either inhibiting the EGF receptor tyrosine kinase with AG1478 or inhibiting the mitogen-activated protein kinase pathway with PD98059. In response to treatment with EGF, the EGF receptor was phosphorylated, which was correlated with phosphorylation and activation of p42/44 mitogen-activated protein kinases. Inhibition of EGF receptor phosphorylation and mitogen-activated protein kinase activation resulted in a reversal of the EGF-induced inhibition of bromodeoxyuridine incorporation and cell cycle arrest. Subsequent studies revealed that the activation of the EGF receptor and the mitogenactivated protein kinase pathway in epithelioid cells induced expression of the cell cycle inhibitory protein p27 Kip1 but not p21 Cip1 . Taken together, our data demonstrate that the EGF receptor is abundantly expressed in epithelioid vascular smooth muscle cells and that the activation of this receptor results in cell cycle arrest through activation of the mitogen-activated protein kinase pathway.

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Telomerase overexpression in K562 leukemia cells protects against apoptosis by serum deprivation and double-stranded DNA break inducing agents, but not against DNA synthesis inhibitors

Cited by 65 publications

References 27 publications

Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis

Epidermal Growth Factor Induction of Phenotype-dependent Cell Cycle Arrest in Vascular Smooth Muscle Cells Is through the Mitogen-activated Protein Kinase Pathway

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