ProfessorOffice: MRb 281Phone: 970-491-0420Website: http://www.nyborglab.comEducation: Ph.D., University of California, RiversideEmail: email@example.comResearch Title: Transcriptional Deregulation in Leukemia Cells
The human T-cell leukemia virus (HTLV-I) is associated with a variety of clinical disorders, including an aggressive and fatal malignancy called adult T-cell leukemia (ATL). It is estimated that between 11 and 20 million people worldwide are infected with HTLV-I, and while most infected individuals remain asymptomatic, a small percentage develop ATL. A single HTLV-I-encoded protein, called Tax, has been strongly implicated in the etiology of the disease. Tax is critical to the viral life cycle, as it activates HTLV-I transcription. Recent studies demonstrate that the cellular coactivator CBP/p300 associates with Tax to potentiate transcriptional activation of the viral genome. CBP/p300 is a coactivator that regulates transcription through interaction with a wide variety of structurally unrelated transcription factors. CBP/p300 belongs to a novel class of recently described transcriptional coactivators proteins that possess histone acetyltransferase (HAT) activity, and appear to play a role in gene-specific activation through modulation of chromatin structure. Although the precise role of the HAT activity of CBP/p300 is unknown, there is a strong link between abnormalities in acetylase function, aberrant chromatin acetylation, and human cancers. These observations suggest that alterations in expression of CBP/p300 expression and/or function is a common denominator in many human malignancies, especially leukemias.
The strong correlation between CBP/p300 deregulation and human malignancies forms the basis for the premise that the physical interaction between CBP/p300 and Tax plays a causal role in neoplastic transformation of the HTLV-I infected T-cell. My laboratory is exploring CBP/p300 transcription function using both in vitro and in vivo approaches. Our methods should allow biochemical dissection of the Tax-CBP/p300 interactions that accompany transcriptional activation. The outcome of our research may reveal basic aspects of CBP/p300 and Tax function as they pertain to gene regulation, chromatin structure, and leukemogenesis.
Sharma, N. and Nyborg, J.K. The Coactivators CBP/p300 and the Histone Chaperone NAP-1 Promote Transcription-Independent Nucleosome Eviction at the HTLV-1 Promoter. Proc. Natl. Acad. Sci. USA 105, 7959-7963 (2008).
Geiger, T.R., Sharma, N., Kim, Y.-M., and Nyborg, J.K. The HTLV-1 Tax Protein Confers CBP/p300 Recruitment and Transcriptional Activation Properties to Phosphorylated CREB. Mol. Cell. Biol. 28, 1383-1392 (2008).
Kim, Y.-M., Sharma, N. and Nyborg, J.K. Tax and the Proto-Oncogene Bcl-3 Form a Complex that Represses HTLV-I Transcription via Displacement of p300. J Virol. 82, 11939-11947 (2008).
Xie, Z., Geiger, T.R., Johnson, E.N., Nyborg, J.K. and Druey, K.M. RGS13 acts as a nuclear repressor of CREB. Molecular Cell, 31, 660-670 (2008).
Ramírez, J.A. and Nyborg, J.K. Molecular Characterization of the HTLV-1 Tax Interaction with the KIX Domain of CBP/p300. J. Mol. Biol. 372, 958-969 (2007).
Lopez, D.I., Mick, J.E., and Nyborg, J.K. Purification of CREB to Apparent Homogeneity: Removal of Truncation Products and Contaminating Nucleic Acid. Protein Expression and Purification 55, 406-418 (2007).
Sharma, N., Lopez, D.I. and Nyborg, J.K. DNA Binding and Phosphorylation Induce Conformational Alterations in the Kinase Inducible Domain of CREB: Implications for the Mechanism of CREB Transcription Function. J. Biol. Chem. 282, 19872-19883 (2007).
Kim, Y.-M., Ramírez, J.A., Mick, J.E., Giebler, H.A., Yan, J.-P. and Nyborg, J.K. Molecular Characterization of the Tax-containing HTLV-1 Enhancer Complex Reveals a Prominent Role for CREB Phosphorylation in Tax Transactivation. J. Biol. Chem. 282, 18750-18757 (2007).
Lemasson, I., Lewis, M., Hivin, P., Cavanagh, M-H., Polakowski, N., Thébault, S., Barbeau, B., Nyborg, J.K. and Mesnard, J.M. HTLV-1 bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription. J. Virology 81, 1543-1553 (2007).
Konesky, K.L., Nyborg, J.K. and Laybourn, P.J. Tax Abolishes Histone H1 Repression of p300 Acetyltransferase Activity at the HTLV-I Promoter. J. Virology, 80, 10542-10553 (2006).
Lemasson, I., Polakowski, N., Laybourn, P.J. and Nyborg, J.K. Tax-Dependent Displacement of Nucleosomes During transcriptional Activation of Human T-cell Leukemia Virus Type 1. J. Biol. Chem. 281,13075-13082 (2006).