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Inactivation of hTERT transcription by Tax Julien Daniel, Raphael Doineau, Astrild Vaudaine, Sebastian Schmidt, Sebastian Olényi Gabet et al., Oncogene 2003 Leukemia-causing? - Blood cancer - telomere dysfunction generates dicentric and multicentric chromosomes - T-cell leukemia virus type 1(HTLV -1) - 3–5% of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) - oncoprotein Tax The idea - telomere dysfunction observed in solid tumors - E-boxes also implicated in the Taxassociated transcriptional inhibition of several cellular genes (p53) -> Telomeraseinactivation? TRAP = Telomerase Repeat Amplification Protocol Cell lysate Differential telomere length or quantity Detection (ELISA, X-ray of radioactively marked probes, ...) Amplified, marked telomeres PCR with labelling of telomere repeats TRAP = Telomerase Repeat Amplification Protocol Cell lysate Differential telomere length or quantity Detection of the original amount of telomere repeats from the RTPCR-procedure RT-PCR with telomereprimers and detection Amplification measured by real-time PCR ➔ Importance of Tax in the decrease of telomerase activity Effect of Tax on hTERT promoter-luciferase ➔ ➔ Tax reduces luciferase activity hTERT is repressed by Tax 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 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