Down-regulation of telomerase activity is an early event of cellular differentiation without apparent telomeric DNA change

Takanashi, Minoko; Ujihara, Makoto; Mizoguchi, Hideaki

doi:10.1016/s0145-2126(98)00065-4

Cited by 30 publications

(25 citation statements)

References 25 publications

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“…Total RNA was isolated using Isogen (Nippongene), and cDNA was synthesized using the Advantage RT-for-PCR Kit (Clontech) as reported previously (21). The resulting cDNA (25 ng) was subjected to PCR amplification.…”

Section: Reverse Transcription Pcrmentioning

confidence: 99%

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

Yamada

Ozaki

Akiyama

et al. 2012

Molecular Cancer Therapeutics

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Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/ mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.

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Section: Reverse Transcription Pcrmentioning

confidence: 99%

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

Yamada

Ozaki

Akiyama

et al. 2012

Molecular Cancer Therapeutics

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“…The catalytic activity is provided by a large protein identified as hTERT (human telomerase reverse transcriptase) that shares homologies with viral reverse transcriptases but also contains distinct motifs conserved in all telomerase complexes identified to date. [7][8][9] Telomerase is present in germ cells but its activity is extinguished during early embryonic development 10,11 and differentiation [12][13][14] and, consequently, is absent from most adult tissues. Limited telomerase activity is observed in some progenitor cells 15 of hematopoietic, 16,17 epithelial, 18,19 and gut origin, [20][21][22] as well as in mitotically active segments of hair follicles.…”

Section: Introductionmentioning

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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“…Generally, the presence of telomerase activity is associated with the undifferentiated state and cellular immortality, while cellular aging and senescence result in cells that lack telomerase (reviewed by Greider 1998). Telomerase levels are quite high in mammalian embryos (Betts & King 1999) but diminish during cellular differentiation (Yamada et al 1998), thus making it a good marker for assessing nuclear reprogramming efficiency during cloned embryo development X-chromosome reactivation in donor cells (Betts et al 2001). We have demonstrated that using hypomethylated donor somatic cells increases the developmental potential of the resultant SCNT embryos possibly by enhancing the nuclear reprogramming efficiency as evident by increased telomerase activity levels.…”

Section: Effect Of Sah Treatment On Scnt Embryo Developmentmentioning

confidence: 99%

S-adenosylhomocysteine treatment of adult female fibroblasts alters X-chromosome inactivation and improves in vitro embryo development after somatic cell nuclear transfer

Jeon

Coppola²,

Perrault³

et al. 2008

Reproduction

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The poor outcome of somatic cell nuclear transfer (SCNT) is thought to be a consequence of incomplete reprogramming of the donor cell. The objective of this study was to investigate the effects of treatment with S-adenosylhomocysteine (SAH) a DNA demethylation agent, on DNA methylation levels and X-chromosome inactivation status of bovine female fibroblast donor cells and the subsequent impact on developmental potential after SCNT. Compared with non-treated controls, the cells treated with SAH revealed (i) significantly (P!0.05) reduced global DNA methylation, (ii) significantly (w1.5-fold) increased telomerase activity, (iii) diminished distribution signals of methylated histones H3-3mK9 and H3-3mK27 on the presumptive inactive X-chromosome (Xi), (iv) alteration in the replication pattern of the Xi, and (v) elevation of transcript levels for X-chromosome linked genes, ANT3, MECP2, XIAP, XIST, and HPRT. SCNT embryos produced with SAH-treated donor cells compared with those derived from untreated donor cells revealed (i) similar cleavage frequencies, (ii) significant elevation in the frequencies of development of cleaved embryos to hatched blastocyst stage, and (iii) 1.5-fold increase in telomerase activity. We concluded that SAH induces global DNA demethylation that partially reactivates the Xi, and that a hypomethylated genome may facilitate the nuclear reprogramming process. Reproduction (2008) 135 815-828

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Down-regulation of telomerase activity is an early event of cellular differentiation without apparent telomeric DNA change

Cited by 30 publications

References 25 publications

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

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

S-adenosylhomocysteine treatment of adult female fibroblasts alters X-chromosome inactivation and improves in vitro embryo development after somatic cell nuclear transfer

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