Luwen Zhang, PhD
Research Interests:
Epstein-Barr virus (EBV) is a human herpesvirus of increasing
medical importance. EBV infection has been associated with the
development of several human cancers. In immunocompromised individuals,
such as organ transplant recipients or AIDS patients, EBV almost
certainly causes two fatal cancers: post-transplantation lymphoproliferative
disorder (PTLD) and AIDS-associated central nerve system (CNS)
lymphoma.
Interferon regulatory factors (IRFs) are a small family of transcriptional
factors with multiple functions including but not limited to host
defense, oncogenesis, apoptosis, viral latency, as well as immune
responses.
We were the first to discover the interferon regulatory factor
7 (IRF-7), to identify the first functional interferon stimulated
response element (ISRE) in a mammalian viral promoter, and to unearth
a novel signal pathway related to IRF-7. In general, the functional
importance of IRF-7 is indicated by: (i) IRF-7 and EBV latency
have an intimate relation: an EBV latency protein induces the expression
of IRF-7, modifies IRF-7 protein by phosphorylation, and relocates
IRF-7 protein from the cytoplasm into the nucleus; and (ii) IRF-7
is a primary inducer of interferon (IFN) genes upon viral infection.
IFNs are essential factors for the host to control and eliminate
viral infection. Thus, IRF-7 holds key information for virus-cell
interactions, the understanding of which is an essential step for
treatment and preventive measures against viral diseases. Our major
interests are to understand the biological roles of IRF-7, and
to explore the treatments for EBV-triggered cancers. The research
will be a blend of virology, molecular and cellular biology, immunology,
and pathology. Major interests are:
1) The functions and regulations of IRF-7 in EBV transformation. EBV transforms human primary B cells in tissue culture and establishes
latency. The transformation process offers the best available system
to examine the biological roles and regulations of IRF-7. We will
take both genetic and biochemical manipulations to identify the
target genes of IRF-7 and to dissect the involvement of cellular
factors and signaling pathways in the regulation of IRF-7 and their
roles in EBV-mediated oncogenesis.
2) The interaction between EBV and HHV8. Human herpesvirus 8 (HHV8)
is also called Kaposi's sarcoma-associated herpesvirus (KSHV) because
it was first discovered in KS specimens and is believed to be the
etiological agent of KS. Interestingly, HHV-8 is implicated in
the pathogenesis of AIDS-associated body cavity-based lymphoma
(BCBL), and the majority of BCBL cells are also coinfected with
EBV. The relationship between the two viruses is under investigation.
3) Potential treatment of human cancers. Currently, there are
no effective treatments for EBV-triggered tumors. We are testing
a novel approach to specifically block the viral transformation
events that lead to the development of human cancers. Our strategy
targets an EBV protein that is required for the viral oncogenesis.
The method may be developed into a novel cancer therapy.
Publications:
Zhang, L., Qi Zou, and Bing-song Cheng. 1987a. Tissue
culture of Polygonum multiflorum. Plant Physiology Communications
(Chinese) 1: 28.
Zhang, L., Qi Zou, and Bing-song Cheng. 1987b.
Plantlet regeneration of Saxifraga stoloniferta. Plant Physiology
Communications (Chinese) 6:48.
Zhang, L., P. M. Mohan, and R.
Padmanabhan. 1992. Processing and localization of Dengue virus
type 2 polyprotein precursor NS3-NS4A-NS4B-NS5. J. Virol 66:7549-54.
Zhang,
L., and R. Padmanabhan. 1993. Role of protein conformation in
the processing of dengue virus type 2 nonstructural polyprotein
precursor. Gene 129:197-205
Kapoor, M., Zhang, L., M. Ramachandra,
J. Kusukawa, K. Ebner, and Radha Padmanabhan. 1995. Association
between NS3 and NS5 proteins of dengue virus type 2 in the putative
RNA replicase is linked to differential phosphorylation of NS5.
J Biol Chem 270:19100-19106.
Kapoor, M., Zhang, L., P. M. Mohan,
and R. Padmanabhan. 1995. Synthesis and characterization of an
infectious RNA encoding dengue virus type 2 genome (New Guinea
C strain). Gene 162:175-180.
Ide*, Y., Zhang*, L., Chen, M., Inchauspe,
G., Bahl., C., Sasaguri, Y., and R. Padmanabhan. 1996. Characterization
of the nuclear localization signal and subcellular distribution
of hepatitis C virus nonstructural protein NS5A. Gene 182:203-211.
* equal contribution.
Zhang, L. and J.S. Pagano. 1997. IRF-7,
a new interferon regulatory factor associated with Epstein-Barr
virus latency. Mol. Cell. Biol. 17:5748-5757.
Zhang, L. and J.S.
Pagano. 1999. Interferon regulatory factor 2 represses the Epstein-Barr
virus BamH I Q latency promoter in type III latency. Mol. Cell.
Biol. 19:3216-23.
Zhang, L. and J.S. Pagano. 2000. Interferon
regulatory factor 7 is induced by Epstein-Barr virus latent membrane
protein 1. J. Virol. 74:5748-57.
Zhang, L. 2000. Gradient temperature
hybridization for RNase protection assays. Molecular Biotechnology
14:73-75.
Zhang, L. and J.S. Pagano. 2001. Interferon regulatory
factor 7 mediates the activation of the transporter associated
with antigen processing 2 (Tap-2) by Epstein-Barr virus latent
membrane protein 1. J. Virol. 75:341-350.
Zhang, L. and J.S.
Pagano. 2001. Interferon Regulatory Factor 7: a Key Cellular
Mediator of LMP-1 in EBV Latency and Transformation. Seminars in
Cancer Biology 11:445-53.
Zhang, L., L. Wu, K. Hong, and J.S. Pagano.
Intracellular signaling molecules activated by Epstein Barr virus
for induction of interferon regulatory factor 7. J. Virol. 75:12393-401.
2001.
Zhang, L. and J.S. Pagano. Structure and Function of Interferon
Regulatory Factor 7. J Interferon Cytokine Res. 22: 95-101. 2002.
Zhang,
L. and J.S. Pagano. Interferon Regulatory Factor 7 and Virus-Cell
Interactions. Recent Research Developments in Molecular and Cellular
Biology. 3:235-241. 2002.
Zhang, L. ,Ke Hong, Jun Zhang, and Joseph
S. Pagano. Multiple signal transducers and activators of transcription
(STATs) are induced by EBV LMP-1. Virology. 323:141-152. 2004.
Zhang,
J., S. Das, C. Kotalik,, A. Patnaik, and Luwen Zhang. The latent
membrane protein 1 of Epstein-Barr virus establishes an antiviral
state via induction of interferon-stimulated genes. J Biol Chem.
2004. 279:46335-46342. 2004.
Zhang, L., J. Zhang, Q. Lambert,
C. J. Der, L. Del Valle, J. Miklossy, K. Khalili, Y. Zhou,and
J. S. Pagano. Interferon regulatory factor 7 is associated with
EBV-transformed CNS lymphoma and has oncogenic properties. J. Vriol.
12987-12995. 2004.
Wang J, Zhang J, Zhang L, Harrington W Jr, West
JT, Wood C. Modulation of Human Herpesvirus 8/Kaposi's Sarcoma-Associated
Herpesvirus Replication and Transcription Activator Transactivation
by Interferon Regulatory Factor 7. J Virol. 79:2420-31. 2005.
Zhang,
J., J. Wang, C. Wood, and Luwen Zhang. KSHV/HHV-8 replication
and transcription activator (RTA) regulates both viral and cellular
genes via interferon-stimulated response element (ISRE). J.Virol.
2005. In press.
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