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Inactivation of hTERT transcription by Tax

Inactivation of hTERT transcription by Tax. Julien Daniel, Raphael Doineau, Astrild Vaudaine, Sebastian Schmidt, Sebastian Olényi Gabet et al., Oncogene 2003. Leukemia-causing?.

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Inactivation of hTERT transcription by Tax

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  1. Inactivation of hTERT transcription by Tax Julien Daniel, Raphael Doineau, Astrild Vaudaine, Sebastian Schmidt, Sebastian Olényi Gabet et al., Oncogene 2003

  2. Leukemia-causing? Blood cancer- telomere dysfunctiongenerates dicentric and multicentric chromosomes- T-cell leukemia virus type1(HTLV -1) - 3–5% of infected individuals develop adultT-cell leukemia/lymphoma (ATLL) - oncoprotein Tax

  3. The idea - telomere dysfunction observed in solid tumors- E-boxes also implicated in the Tax-associatedtranscriptional inhibition of several cellular genes (p53) -> Telomerase-inactivation?

  4. Cell lysate TRAP = Telomerase Repeat Amplification Protocol Differential telomere length or quantity PCR with labelling of telomere repeats Detection (ELISA, X-ray of radioactively marked probes, ...) Amplified, marked telomeres

  5. Cell lysate TRAP = Telomerase Repeat Amplification Protocol Differential telomere length or quantity RT-PCR with telomere-primers and detection Detection of the original amount of telomere repeats from the RT-PCR-procedure

  6. Amplification measured by real-time PCR • Importance of Tax in the decrease of telomerase activity

  7. Effect of Tax on hTERT promoter-luciferase • Tax reduces luciferase activity • hTERT is repressed by Tax

  8. Discussion - Outview „Paradoxical“ role of TAX: • activates T-cell proliferation; in normal T-cells, hTERT is activated • At the same time, it blocks hTERT transcription • Thus, Tax favours chromosome rearrangement and mutation accumulation, leading to malignant cells • Tax expression is restricted to the pre-malignant stage where it inhibits the „reparatory effect“ of hTERT

  9. Discussion - Outview • Many other forms of cancer are also preceded by a long latency • There seem to exist other oncogenes exhibiting the same role as Tax • Thus, better examination of the Tax mechanism may provide insights into other forms of cancer

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