Inactivation of hTERT transcription by Tax

Julien Daniel, Raphael Doineau, Astrild Vaudaine, Sebastian Schmidt, Sebastian Olényi

Gabet et al., Oncogene 2003

- Blood cancer

- telomere dysfunctiongenerates dicentric and multicentric

chromosomes

- T-cell leukemia virus type1(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-associatedtranscriptional 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