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Antagonistic effect of the tumor suppressor Menin and the HBZ protein of HTLV-1 on telomerase activity

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Antagonistic effect of the tumor suppressor Menin and

the HBZ protein of HTLV-1 on telomerase activity

Anne-Sophie Kuhlmann, Sophie Girard, Louis Gazzolo, Madeleine Dodon

To cite this version:

Anne-Sophie Kuhlmann, Sophie Girard, Louis Gazzolo, Madeleine Dodon. Antagonistic effect of

the tumor suppressor Menin and the HBZ protein of HTLV-1 on telomerase activity. Frontiers of

Retrovirology: Complex retroviruses, retroelements and their hosts, Sep 2009, Montpellier, France.

pp.P33, �10.1186/1742-4690-6-S2-P33�. �inserm-00663601�

(2)

BioMed Central

Page 1 of 1

(page number not for citation purposes)

Retrovirology

Open Access

Poster presentation

Antagonistic effect of the tumor suppressor Menin and the HBZ

protein of HTLV-1 on telomerase activity

Anne-Sophie Kuhlmann*

1,2,3

, Sophie Girard

2,3

, Louis Gazzolo

1,2,3

and

Madeleine Duc Dodon

1,2,3

Address: 1Virologie Humaine, INSERM-U758, 69364 Lyon Cedex 07, France, 2Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France

and 3IFR 128 BioSciences Lyon-Gerland, 69364 Lyon Cedex 07, France

* Corresponding author

Background

HTLV-1 is a retrovirus responsible for adult T-cell leuke-mia (ATL) in 5% of infected people. ATL is characterised by a monoclonal proliferation of infected CD4+ T lym-phocytes in which a high telomerase activity associated to a poor prognosis has been observed [1]. Furthermore, HBZ is the only viral protein clearly detectable in all ATL patient samples. This protein has been shown to up-regu-late the transcription of the catalytic subunit of telomer-ase, hTERT. Therefore interaction of HBZ with AP-1 transcription factor JunD on the proximal promoter of hTERT is required to up-regulate the gene [2].

Menin, a tumor suppressor, is known as a repressor of both JunD transcriptional activity [3] and hTERT tran-scription [4]. These data led us to investigate the mecha-nisms underlying hTERT up-regulation by HBZ and JunD in the presence of Menin.

Results

Thus we have shown that HBZ is able to counteract the inhibitory effect exerted by Menin on JunD transcrip-tional activity in a dose dependent manner. HBZ is also able to partially restore endogenous telomerase activity in spite of the Menin presence. HBZ and JunD have been shown to co-immunoprecipitate with Menin protein sug-gesting that HBZ does not counteract Menin by evicting it from the complex. Menin repress JunD transcriptional activity through the recruitment of histone deacetylases

whereas HBZ interacts with p300, an histone acetyl trans-ferase. Thus we have demonstrated that p300 recruitment by HBZ is necessary to stimulate JunD transcriptional activity and hTERT proximal promoter in the presence of Menin.

Similarly to hTERT and JunD which are highly expressed in ATL cells, Menin mRNA are clearly detectable in pri-mary ATL cells underlying the importance for HBZ to be able to counteract the repression exerted by this tumor suppressor.

Conclusion

Our findings provide further insights in the the mecha-nism of hTERT up-regulation by JunD and HBZ and ascer-tain Menin as a new player in the ATL leukemogenic process.

References

1. Kubuki Y, Suzuki M, Sasaki H, Toyama T, Yamashita K, Maeda K, Ido A, Matsuoka H, Okayama A, Nakanishi T, Tsubouchi H: Leuk

Lym-phoma 2005, 46:393-9.

2. Kuhlmann AS, Villaudy J, Gazzolo L, Castellazzi M, Mesnard JM, Duc Dodon M: Retrovirology 2007, 4:92.

3. Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL: Cell 1999, 96:143-52.

4. Lin SY, Elledge SJ: Cell 2003, 113:881-9.

from Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts

Montpellier, France. 21-23 September 2009 Published: 24 September 2009

Retrovirology 2009, 6(Suppl 2):P33 doi:10.1186/1742-4690-6-S2-P33

<supplement> <title> <p>Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts</p> </title> <note>Meeting abstracts - A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1742-4690-6-S2-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1742-4690-6-S2-info.pdf</url> </supplement>

This abstract is available from: http://www.retrovirology.com/content/6/S2/P33 © 2009 Kuhlmann et al; licensee BioMed Central Ltd.

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