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

- 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 Leukemia-causing?

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

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

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

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