B.S., University of Montpellier II, France
M.S., University of Montpellier I, France
Ph.D., University of Montpellier I, France
Approximately 20 million people are infected with Human T-cell Leukemia Virus type 1 (HTLV-1), and about 6% of this population will develop a pathology associated with this retrovirus. One of these diseases is called adult T-cell leukemia/lymphoma (ATLL). ATLL is an aggressive and often fatal proliferation of T CD4+ lymphocytes that can occur after a viral latency period of more than twenty years. To date, there is no effective treatment for ATLL, and individuals diagnosed with the most severe stage of the disease have a mean survival time of six months. The molecular mechanisms leading to the development of ATLL are unclear, although the virally-encoded protein Tax is postulated to have a role in disease progression. The low percentage of infected individuals who develop ATLL and the long latency period suggest that multiple events are required for T-cell transformation. Therefore, defining the mechanisms through which HTLV-1 infection leads to ATLL will increase our understanding of the cellular transformation process in general.
Our research focuses on characterizing the roles of the virally-encoded proteins Tax and HBZ in HTLV-1 transcriptional regulation and in the disruption of cellular gene expression. Tax functions as a transcription factor and, in conjunction with a number of cellular factors that include members of the ATF/CREB family, strongly activates transcription of the HTLV-1 genome. Tax also has oncogenic properties that stem from its ability to deregulate transcription of a number of cellular genes. Less is known about the HBZ protein, which was identified only recently. To date, HBZ has been shown to repress transcription through its interaction with a subset of cellular bZIP proteins, including certain ATF/CREB members. Of specific interest to us is the ability of HBZ to repress transcription driven by the HTLV-1 promoter. In order to define the functions of Tax and HBZ in viral infection, we are analyzing protein/DNA interactions within the cell and in vitro, and determining how these viral proteins affect transcription.
Polakowski N., Gregory H., Mesnard J.M. and Lemasson I. (2010). Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain. Retrovirology, 7(1):61.
Halin M., Douceron E., Clerc I., Journo C., Ko N.G., Landry S., Murphy E.L., Gessain A., Lemasson I., Mesnard J.M., Barbeau B. and Mahieux R. (2009). Human T-cell Leukemia Virus Type 2 produces a spliced antisense transcript encoding a protein that lacks a classical bZIP domain but still inhibits Tax2-mediated transcription. Blood, 114:2427-2438.
Clerc I., Hivin P., Rubbo P.A., Lemasson I., Barbeau B. and Mesnard J.M. (2009). Propensity for HBZ-SP1 isoform of HTLV-I to inhibit c-Jun activity correlates with sequestration of c-Jun into nuclear bodies rather than inhibition of its DNA-binding activity. Virology, 391:195-202.
Landry S., Halin M., Vargas A., Lemasson I., Mesnard J.M. and Barbeau B. (2009). Upregulation of HTLV-1 antisense transcription by the viral Tax protein. J. Virol., 83 (4):2048-54.
Clerc I., Polakowski N., André-Arpin C., Cook P., Barbeau B., Mesnard J.M. and Lemasson I. (2008). An interaction between the human T cell leukemia virus type 1 basic leucine zipper factor (HBZ) and the KIX domain of p300/CBP contributes to the down-regulation of tax-dependent viral transcription by HBZ. J. Biol. Chem., 283 (35):23903-23913.
Lemasson I., Lewis M., Polakowski N., Hivin P., Cavanagh M.H., Thébault S., Barbeau B., Nyborg J.K. and Mesnard J.M. (2007). HTLV-1 bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription. J. Virol., 81 (4):1543-1553.
Lemasson I., Polakowski N., Laybourn P.J. and Nyborg J.K. (2006). Tax-dependent displacement of nucleosomes during transcriptional activation of human T-cell leukemia virus, type 1. J. Biol. Chem., 281 (19):13075-13082.
Lemasson I., Polakowski N., Laybourn P.J. and Nyborg J.K. (2004). Transcription regulatory complexes bind the human T-cell leukemia virus 5’ and 3’ long terminal repeats to control gene expression. Mol. Cell. Biol., 24 (14):6117-6126.
Lemasson I., Polakowski N., Laybourn P.J. and Nyborg J.K.(2002). Transcription factor binding and histone modifications on the integrated proviral promoter in HTLV-I-infected T-cells. J. Biol. Chem., 277 (51): 49459-49465.
Lemasson I. and Nyborg J.K. (2001). HTLV-I Tax repression of p73b is mediated through competition for the C/H1 domain of CBP. J. Biol. Chem., 276 (19): 15720-15727.
Giebler H., Lemasson I. and Nyborg J.K. (2000). P53 recruitment of CBP mediated through phosphorylated CREB: a novel pathway for tumor suppressor regulation. Mol. Cell. Biol., 20 (13):4849-4858.
Lemasson I., Thébault S., Sardet C., Devaux C. and Mesnard J.M. (1998). Activation of E2F-mediated transcription by human T-cell leukemia virus type I Tax protein in a p16INK4A negative T-cell line. J. Biol. Chem., 273 (36):23598-23604.
Lemasson I., Robert-Hebmann V., Hamaia S., Duc Dodon M., Gazzolo L. and Devaux C. (1997). Transrepression of lck gene expression by human T-cell leukemia virus type I-encoded p40tax. J. Virol., 71:1975-1983.