Regulation and Effects of Modulation of Telomerase Reverse Transcriptase Expression in Primordial Germ Cells During Development1

Coussens, Matthew J.; Yamazaki, Yukiko; Moisyadi, Stefan; Suganuma, Ryota; Yanagimachi, Ryuzo; Allsopp, Richard

doi:10.1095/biolreprod.106.052167

Cited by 20 publications

(18 citation statements)

References 39 publications

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“…The hTERT promoter is recognized to be a cancer-specific promoter for various cancers, while it is also activated in the germ line 29,30 . The hUPII promoter is a bladder-specific promoter that can only drive gene expression in urothelium cells 31,32 .…”

Section: Discussionmentioning

confidence: 99%

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

et al. 2014

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The conventional strategy for cancer gene therapy offers limited control of specificity and efficacy. A possible way to overcome these limitations is to construct logic circuits. Here we present modular AND gate circuits based on CRISPR-Cas9 system. The circuits integrate cellular information from two promoters as inputs and activate the output gene only when both inputs are active in the tested cell lines. Using the luciferase reporter as the output gene, we show that the circuit specifically detects bladder cancer cells and significantly enhances luciferase expression in comparison to the human telomerase reverse transcriptase-renilla luciferase construct. We also test the modularity of the design by replacing the output with other cellular functional genes including hBAX, p21 and E-cadherin. The circuits effectively inhibit bladder cancer cell growth, induce apoptosis and decrease cell motility by regulating the corresponding gene. This approach provides a synthetic biology platform for targeting and controlling bladder cancer cells in vitro.

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Section: Discussionmentioning

confidence: 99%

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

et al. 2014

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“…Concentration and purity of the extracted RNA were determined using the A260/A280 value measured on an ND1000 Spectrophotometer (NanoDrop Technologies). Real-time RT-PCR analysis of gene expression was performed as described (47).…”

Section: Methodsmentioning

confidence: 99%

“…Telomerase activity was quantitatively assessed by the telomere repeat amplification protocol (TRAP) assay using the TRAPeze telomerase detection kit (Chemicon) as described (47).…”

Section: Methodsmentioning

confidence: 99%

RNAi screen for telomerase reverse transcriptase transcriptional regulators identifies HIF1α as critical for telomerase function in murine embryonic stem cells

Coussens

Davy

Brown³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In various types of stem cells, including embryonic stem (ES) cells and hematopoietic stem cells, telomerase functions to ensure long-term self-renewal capacity via maintenance of telomere reserve. Expression of the catalytic component of telomerase, telomerase reverse transcriptase (Tert), which is essential for telomerase activity, is limiting in many types of cells and therefore plays an important role in establishing telomerase activity levels. However, the mechanisms regulating expression of Tert in cells, including stem cells, are presently poorly understood. In the present study, we sought to identify genes involved in the regulation of Tert expression in stem cells by performing a screen in murine ES (mES) cells using a shRNA expression library targeting murine transcriptional regulators. Of 18 candidate transcriptional regulators of Tert expression identified in this screen, only one candidate, hypoxia inducible factor 1 alpha (Hif1α), did not have a significant effect on mES cell morphology, survival, or growth rate. Direct shRNA-mediated knockdown of Hif1α expression confirmed that suppression of Hif1α levels was accompanied by a reduction in both Tert mRNA and telomerase activity levels. Furthermore, gradual telomere attrition was observed during extensive proliferation of Hif1α-targeted mES cells. Switching Hif1α-targeted mES cells to a hypoxic environment largely restored Hif1α levels, as well as Tert expression, telomerase activity levels, and telomere length. Together, these findings suggest a direct effect of Hif1α on telomerase regulation in mES cells, and imply that Hif1α may have a physiologically relevant role in maintenance of functional levels of telomerase in stem cells.

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“…To date, telomerase activity has been shown to be specifically expressed in germ cells, immortal cell lines, and most tumor cells [17][18][19][20][21][22]. The telomerase hypothesis suggests that telomerase activity is high in germ cells, whereas this activity decreases in somatic tissues during development and differentiation [23].…”

Section: Introductionmentioning

confidence: 99%

Green tea extracts attenuate doxorubicin-induced spermatogenic disorders in conjunction with higher telomerase activity in mice

Sakai

Sueoka

Tanigaki

et al. 2010

J Assist Reprod Genet

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Purpose The aim of this study was to investigate the protective effect of green tea extracts against doxorubicininduced damage in the mouse testes correlating with telomerase activity. Methods Green tea extracts were administered orally. Doxorubicin was coadministered intraperitoneally. These testes were evaluated histologically and the telomerase activity was analyzed. Additional immunostaining was carried out. Results Both the sperm density and sperm motility were significantly increased in green tea extracts coadministration groups as compared to the doxorubicin-treated groups. By histological analysis, germ cell damage was greatly attenuated by green tea extracts coadministration. Telomerase activity significantly increased in association with the coadministration of green tea extracts as compared to that of doxorubicin-only groups. In all groups, human telomerase reverse transcriptase signals were mainly observed in the spermatocytes and spermatids.Conclusions These findings suggest that green tea extracts exert protective effects against doxorubicin-induced spermatogenic disorders in conjunction with higher telomerase activity levels.

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Regulation and Effects of Modulation of Telomerase Reverse Transcriptase Expression in Primordial Germ Cells During Development1

Cited by 20 publications

References 39 publications

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

RNAi screen for telomerase reverse transcriptase transcriptional regulators identifies HIF1α as critical for telomerase function in murine embryonic stem cells

Green tea extracts attenuate doxorubicin-induced spermatogenic disorders in conjunction with higher telomerase activity in mice

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