Isabelle M. Lemasson
BS, University of Montpellier II, France
MS, University of Montpellier I, France
PhD, 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., Pearce M., Kuguyo O., Boateng G., Hoang K., Lemasson I. (2020). The splice 1 variant of HTLV-1 bZIP factor stabilizes c-Jun. Virology, 549:51-58.
Fazio A.L., Kendle W., Hoang K., Korleski E., Lemasson I.* and Polakowski N*. (2019). HTLV-1 bZIP factor upregulates the expression of ICAM-1 to facilitate HTLV-1 infection. *Corresponding authors. J. Virol., 93(19):e00608-19.
Rushing A.W. Rushing B., Hoang K., Sander S.V., Peloponese J.M. Jr., Polakowski N. and Lemasson I. (2019). The HTLV-1 basic leucine zipper factor upregulates the expression of the antioxidant Heme Oxygenase I. Plos Pathogens, 15(6):e1007922.
Rushing A.W., Hoang K., Polakowski N. and Lemasson. I.(2018). The Human T-Cell Leukemia Virus Type 1 Basic Leucine Zipper Factor Attenuates Repair of Double-Stranded DNA Breaks via Nonhomologous End Joining. J. Virol. 92(15):e00672-18.
Terol M., Gazon H., Lemasson I., Duc Dodon M., Barbeau B, Césaire R., Mesnard J.M. and Peloponese J.M. (2017). HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression. Leukemia, 31(10):2235-2243.
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., 90(7):3600-3610.
Wright D.G., Marchal C., Hoang K., Ankney J.A., Nguyen S.T., Rushing A.W., Polakowski N., Miotto B. and Lemasson I. (2016). HBZ represses p53 function by inhibiting p300/CBP and HBO1 HAT activities. Oncotarget, 7(2):1687-1706.
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.
R21- National Institutes of Health, NIAID (1R21AI166077). “Role of HTLV-1 HBZ in viral infection.” $410,333. 09/22/21-08/31/23. PI: Isabelle Lemasson/Co-I: Nicholas Polakowski.
R15- National Institutes of Health, NIAID (R15AI133412). “A novel role of the viral protein HBZ in mediating HTLV-1 infection.” $435,664 06/26/17-03/31/22. PI: Isabelle Lemasson/Co-I: Nicholas Polakowski.
R21- National Institutes of Health, NIAID (1R21AI133163). “Activation of HMOX1 expression by an HBZ-small Maf complex as a potentialtherapeutic target for HTLV-1 associated diseases.” $405,625. 12/20/17-11/30/19 PI: Isabelle Lemasson/Co-I: Nicholas Polakowski.
Brody School of Medicine Seed/Bridge Grant:Enhanced cell-to-cell transmission of Human T-cell Leukemia Virus type-1 by theviral protein HBZ. $25,000. 08/01/16-07/31/18. PI: Nicholas Polakowski /Co-PI:Isabelle Lemasson
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.
|Abrams, Steve||Research Specialist||Brody 5N-132/134||252-744-2717|
|Hoang, Kimson||Research Specialist||Brody 5N132 /134||252-744-2717|
|Gibson, Gabriel||Research Technician||Brody 5N132 /134||252-744-2717|
|Sarker, Md Abu Kawsar||IDPBS Doctoral Student||Brody 5N132 /134||252-744-2717|
|Fruge, Abby||Volunteer||Brody 5N132 /134||252-744-2717|