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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
- 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