| Budget Amount *help |
¥31,300,000 (Direct Cost: ¥31,300,000)
Fiscal Year 2000: ¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 1999: ¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 1998: ¥11,700,000 (Direct Cost: ¥11,700,000)
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| Research Abstract |
Telomerase is a ribonucleoprotein complex that synthesizes telomeric G-rich strand DNA de novo. It is a specialized reverse transcriptase, containing the catalytic component, TERT and the template RNA, TR.To better understand regulation mechanisms of telomerase, in this study, we first established TERT^<-1-> knockout mice. The first generation of TERT^<-1-> knockout mice did not show any phenotype, indicating that the absence of telomerase catalytic protein by itself does not affect mouse development. However, when TERT^<-1-> mice were mated to keep the line absent for telomerase, the fifth generation mice showed significantly hypotrophic germ line cells. These results indicate that germ cells are particularly sensitive to telomere length reduction. We and others have already demonstrated that TERT gene expression levels have a primary role in regulating telomerase activity in cells. Although it has been reported that several transcription factors, including Myc, Sp1, ER, are involved
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in TERT expression, details of mechanisms regulating TERT, especially in normal somatic cells, remain largely unknown. We have studied normal human peripheral lymphocytes as a model system. We found that the transcription factors USF1 and 2 positively regulate the TERT promoter in vitro. Truncated forms of USF1 and 2, mini-USF1 and mini-USF2, are known to be produced from the same genes by alternative splicing. Interestingly, we demonstrated that mini-USF1 and 2 negatively regulate the promoter in vitro. Human peripheral lymphocytes are mostly resting and do not possess telomerase activity. Upon external stimuli applied to resting lymphocytes, they start proliferation and simultaneously begin to show telomerase activity. We found that the negative regulator, mini-USFs are present in resting cells but not in activated lymphocytes. In contrast, the positive regulator, full length USFs are present both in resting and growing lymphocytes. These results suggest that mini-USFs might have dominant negative effects on full USFs in controlling TERT expression. Less
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