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.
Laverdure S., Polakowski N., Hoang K. and Lemasson I. (2016). Permissive sense
and antisense transcription from the 5' and 3' long terminal repeats of Human
T-cell Leukemia Virus type 1. J. Virol.
JVI.02634-15 [Epub ahead of print].
Wright D.G., Marchal C., Hoang K., Ankney J.A., Nguyen S.T., Rushing A.W., Polakowski N., Miotto B. and Lemasson I. (2015). HBZ represses p53 function by inhibiting p300/CBP and HBO1 HAT activities. Oncotarget, Nov 28. doi: 10.18632/oncotarget.6424.
Polakowski N., Terol M., Hoang K., Nash I., Laverdure S., Gazon H., Belrose G., Mesnard J.M., Césaire R., Peloponese J.M. Jr. and Lemasson I. (2014). HBZ stimulates brain-derived neurotrophic factor/TrkB autocrine/paracrine signaling to promote survival of human T-cell leukemia virus type 1-Infected T cells. J. Virol., 88:13482-13494.
Gazon H., Lemasson I., Polakowski N., Césaire R., Matsuoka M., Barbeau B., Mesnard J.M. and Peloponese J.M. Jr. (2012). Human T-cell leukemia virus type 1 (HTLV-1) bZIP factor requires cellular transcription factor JunD to upregulate HTLV-1 antisense transcription from the 3' long terminal repeat. J. Virol., 86: 9070-9078.
Wurm T., Wright D.G., Polakowski N., Mesnard J.M. and Lemasson I. (2012). The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP. Nucleic Acids Res. 40:5910-5925. This article was selected as a Breakthrough Articles (represent the very best papers of NAR papers in terms of originality, significance and scientific excellence).
Polakowski N., Han H. and Lemasson I. (2011). Direct Inhibition of RNase T2 Expression by the HTLV-1 Viral Protein Tax. Invited submission for a special issue of Viruses: Recent Developments in HTLV Research (article reviewed). Viruses, 3: 1485-1500.
Cook P., Polakowski N. and Lemasson I. (2011). HTLV-1 HBZ protein deregulates interactions between cellular factors and the KIX domain of p300/CBP. J. Mol. Biol., 409: 384-398.
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.
R01- National Institutes of Health, NCI (1R01CA128800). "Regulation of HTLV-1 and cellular gene transcription by the viral protein HBZ." $1,331,505. 02/01/10-06/30/16. PI: Isabelle Lemasson.
R21- National Institutes of Health, NIAID (1R21AI079290-01A1). "Mechanism of HTLV-1 Tax-mediated activation of CDK6 transcription." $358,438. 04/01/09-03/31/12. PI: Isabelle Lemasson.
American Heart Association. "Inhibition of the Coactivator p300 Functions by the Viral Protein HBZ: A Potential Mechanism for Repression of Cardiac Hypertrophy." $154,000. 07/01/09-06/30/11. PI: Isabelle Lemasson.
East Carolina University, Division of Research and Graduate Studies, Research Development Grant Award. "Disruption of histone deacetylase complex functions by the viral oncoprotein Tax during Human T-cell Leukemia Virus type-1 infection". $25,000. 07/01/06-06/30/07. PI: Isabelle Lemasson.
Lemasson Lab 2016