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Kenneth L. Wright, Ph.D. Associate Professor in the Department of Interdisciplinary Oncology Member-in-Residence of the Moffitt Cancer Center Director, Cancer Biology Ph.D. Program E-mail: Ken.Wright@moffitt.org |
Training
B.S.: University of Florida, Chemistry, 1984.
Ph.D.: University of Massachusetts, Worcester, MA, 1990.
Postdoctoral Fellow: Lineberger Comprehensive Cancer Center at University
of North Carolina.
Research
Interests
My primary interest is the molecular mechanisms controlling genes involved
in antigen presentation. Antigen presentation is a key step in eliciting
a normal immune response and it can play an important role in tumor rejection
and autoimmunity. The laboratory is currently focused on CIITA a master
regulator of the MHC Class II family of antigen presentation genes. We
are examining CIITA gene regulation in the two primary cell types. The
first is in B-lymphocytes and during their terminal differentiation into
antibody secreting plasma cells. The second is in primary human and mouse
dendritic cells.
In B-lymphocytes our laboratory has previously mapped the B-cell specific
promoter of CIITA. This was done through a combination of in vivo and
in vitro DNA binding studies. One of the more significant outcomes of
this study was the discovery that the transcriptional silencer PRDI-BF1
down-regulates CIITA and MHC class II expression in multiple myeloma cells.
Multiple myeloma is a disease of malignant plasma cells. PRDI-BF1 also
down-regulates c-myc, Pax5 and interferon-beta expression. The chromosomal
location of PRDI-BF1, 6q21, is deleted in a high percentage of B cell
lymphomas as well as other types of cancer. Our investigations have identified
a natural truncated form of PRDI-BF1 that is lacking a critical N-terminal
domain in multiple myeloma cells and have shown that this isoform is impaired
in repressing CIITA transcription. Deletion of this domain from the other
two PRDI-BF1 family members converts these proteins from growth suppressive
to oncogenic. The role of PRDI-BF1 and its truncated form in the development
and progression of multiple myeloma is currently under investigation.
The mechanism of action of PRDI-BF1 is also being studied. PRDI-BF1 was known to recruit histone deacetylases as part of its transcription repression activity. We have now identified that histone methyltransferases are also recruited by PRDI-BF1 and play an important role in its activity. Histone methyltransferases have recently been shown to play a new and critical role in gene regulation. This methyltransferase activity is specific for histone H3-lysine 9. This finding is consistent with the repressive function of PRDI-BF1 since H3-lysine 9 methylation is exclusively associated with transcriptional silencing. This indicates that PRDI-BF1 may serve as a scaffold molecule to bring multiple chromatin modifying enzymes to specific promoters such as CIITA. Investigations are continuing to dissect the role of the histone methyltransferase in CIITA regulation.
We are also characterizing the dendritic cell specific promoter of CIITA in both human and mouse primary dendritic cells. CIITA transcription is high in immature DC cells but is rapidly turned off when the cells receive a maturation signal. We have identified several key transcription factors required for DC expression. The role of these factors as well as the silencing of expression observed upon dendritic cell maturation is an area of continued investigation using multiple approaches including gene knock-out mouse models. These studies may provide vital information for targeting expression of tumor specific antigens directly to the professional antigen presenting dendritic cell with out altering expression in other cells.
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Selected Publications
Ghosh, N., Piskurich, J.F., Wright, G.M., Hassani, K., Ting, J.P.-Y., and Wright, K.L. (1999).. A novel element and a TEF-2-like element activate the Major histocompatibility complex class II transactivator in B-lymphocytes. J. Biol. Chem., 274, 32342-32350.
Dovhey, S. E., Ghosh, N., and Wright, K. L. (2000). Loss of IFN-g inducibility of TAP1 and LMP2 in a renal cell carcinoma cell line. Cancer Research, 60, 5789-5796.
Ghosh, N., Gyory, I., Wright, G.M., Wood, J., and Wright, K.L. (2001) PRDI-BF1 silences CIITA expression in multiple myeloma cells. J. Biol. Chem., 276:15264-15268.
Ghosh, N. and Wright, K.L. (2001) Loss of TAP and LMP expression in Renal Cell Carcinomas: a mechanism of tumor escape. Cancer Research Alert, 2:109-113.
Gyory, I., Ghosh, N. and Wright, K.L. (2003) Identification of a functionally impaired PRDI-BF1 transcriptional repressor in myeloma cells. J. Immunology 170:3125-3133.
Rezai-Zadeh, N., Zhang, X., Namour, F., Fejer, G., Wen, Y.-D., Yao, Y.-L., Gyory, I., Wright, K.L., Seto, E. (2003) Targeted recruitment of a histone H4-specific methyltransferase by the transcription factor YY1. Genes and Development, 17:1019-1029.
Gyory, I., Wu, J., Fejer G, Seto E, and Wright, K.L. (2004) PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing. Nature Immunology, 5:299-308.
Cancer Biology Ph.D. Program
H. Lee Moffitt Cancer Center, MRC-4 East
12902 Magnolia Drive
Tampa, Florida 33612
Phone: 813-745-6876
E-mail: CancerPHD@moffitt.org
Copyright © 2000 University of South Florida