Faculty & Research

Robert Harrod, Ph.D.

Assistant Professor

Ph.D.: University of Maryland

Postdoctoral training:
National Institutes of Health
USUHS/Naval Medical Center

Office: 334-DLS
Tel: 214.768.3864
Fax: 214.768.3955
Email: rharrod@smu.edu

Lab: 322-DLS
Tel: 214.768.1965

Research Interests

Human Retroviruses/ Mechanisms of Viral Carcinogenesis/ Tumor Biology/ Transcriptional Regulation of Gene Expression

The human immunodeficiency virus type-1 (HIV-1) and human T-cell leukemia/lymphotropic virus type-1 (HTLV-1), infect CD4+ T-lymphocytes and cause Acquired Immune-Deficiency Syndrome (AIDS) and Adult T-cell Leukemia/Lymphoma (ATLL), respectively. The long-term goals of this research are to advance our understanding of the molecular and biochemical events that contribute to retroviral pathogenesis and to identify candidate molecular targets for the development of novel anti-retroviral and/or anti-tumorigenic strategies.

HTLV-1

HTLV-1:
We have demonstrated that the HTLV-1 accessory protein, p30^II, interacts and cooperates with the cellular oncoprotein c-MYC to transactivate c-MYC responsive growth/proliferative genes and induce cellular transformation (Awasthi et al. 2005. Mol. Cell. Biol. 25:6178-6198). Importantly, these findings represent the first evidence that a non-Tax HTLV-1 pX protein cooperates with cellular oncogenes to promote transformation, and suggest that p30^II may contribute to T-cell leukemogenesis associated with the development of acute/lymphoma-stage ATLL through interactions with cellular oncoproteins. The HTLV-1 p30^II protein binds to the transcriptional HTLV-1 coactivators/acetyltransferases p300/CBP and TIP60 and recruits TIP60 to p30^II/c-MYC-containing transcription complexes on promoters of c-MYC responsive genes in HTLV-1-infected T-cell-lines and ATLL patient lymphocytes (Awasthi et al. 2005. Mol. Cell. Biol. 25:6178-6198; Yang et al. 2007, currently submitted). Further, we have demonstrated that p30^II induces Lys-acetylation of the c-MYC oncoprotein associated with transactivation, increased S-phase cell-cycle entry, and cellular transformation (Yang et al. 2007, currently submitted). The ability of p30^II to cooperate with c-MYC is associated with protection against c-MYC-induced apoptosis (programmed cell-death) in the presence of genotoxic stress –which could promote continuous DNA replication and the acquisition of genetic mutations that support oncogenic cell transformation (Yang et al. 2007, currently submitted).

HTLV-1

HIV-1:
Our HIV-related studies focus on (1) host-pathogen molecular interactions and neurotrophin-signaling during HIV neuropathogenesis/NeuroAIDS, associated with HIV-1 infections of the CNS (Harrod et al. 2003. J. Biol. Chem. 278:12310-12318; Wong et al. 2004. J. Biol. Chem. 279:55667-55674; Wong et al. 2005. J. Biol. Chem. 280:9390-9399), and (2) the identification of cellular factors involved in HIV-1 transactivation and retroviral replication (Sharma et al. 2007. J. Biol. Chem. 282:12048-12057). We recently demonstrated that the Werner syndrome helicase (WRN) is an essential cofactor for basal and Tat-activated HIV-1 transcription (Sharma et al. 2007. J. Biol. Chem. 282:12048-12057). The WRN protein interacts with the HIV-1 transactivator, Tat, in chromatin-remodeling complexes recruited to the retroviral LTR in HIV-1-infected T-lymphocytes as demonstrated by ChIP analyses. Inhibition of WRN functions –through co-expression of a dominant-negative WRNK577M mutant protein, blocked approx 95% of retroviral replication in transfected FACS-isolated HIV-1-infected T-lymphocytes (Sharma et al. 2007. J. Biol. Chem. 282:12048-12057), suggesting that WRN may be a plausible molecular target for the development of anti-retroviral/AIDS therapeutic inhibitors. We are currently working to develop small-molecule chemical inhibitors of WRN as a basis to prevent the replication of multi-drug-resistant HIV/AIDS.

Selected Publications

H. Yang, Awasthi, S., Thammavaram, C. K., Khan, S., Chan, S., Harrod, C. K., Ratner, L., Lairmore, M. D., Martinez, E., Faiola, F., Luscher, B., Takemoto, S., Robson, C. N., Henriksson, M., and R. Harrod (2007). Modulation of c-MYC oncogenic transformation by acetylation during retroviral carcinogenesis: cooperation between c-MYC and HTLV-1 p30^II oncoproteins. Currently submitted

T. L.-N. Nguyen, de Walque, S., Veithen, E., Deckoninck, A., Martinelli, V., de Launoit, Y., Burny, A., Harrod, R., and C. Van Lint (2007). Transcriptional regulation of the bovine leukemia virus promoter by the cyclic AMP response element modulator tau isoform. J. Biol. Chem. 282:20854-20867

A. Sharma, Awasthi, S., Harrod, C. K., Matlock, E. F., Khan, S., Xu, L., Chan, S., Yang, H., Thammavaram, C. K., Rasor, R. A., Burns, D. K., Skiest, D. J., Van Lint, C., Girard, A.-M., McGee, M., Monnat, R. J., Jr., and R. Harrod (2007). The Werner syndrome helicase is a cofactor for HIV-1 long terminal repeat transactivation and retroviral replication. J. Biol. Chem. 282:12048-12057

S. Awasthi, Sharma, A., Wong, K., Zhang, J., Matlock, E. F., Rogers, L., Motloch, P., Takemoto, S., Taguchi, H., Cole, M. D., Luscher, B., Dittrich, O., Tagami, H.,Nakatani, Y., McGee, M., Girard, A.-M., Gaughan, L., Robson, C. N., Monnat, R. J., Jr., and R. Harrod (2005). An HTLV-1 enhancer of MYC transforming potential stabilizes MYC-TIP60 transcriptional interactions. Mol. Cell. Biol. 25:6178-6198

C. Nicot, Harrod, R. L., Ciminale, V. and G. Franchini (2005). Human T-cell leukemia/lymphoma virus type 1 nonstructural genes and their functions. Oncogene 24:6026-6034

K. Wong, Sharma, A., Awasthi, S., Matlock, E. F., Rogers, L., Van Lint, C., Skiest, D. J., Burns, D. K., and R. Harrod (2005). HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin-signaling through CREB. J. Biol. Chem. 280:9390-9399

K. Wong, Zhang, J., Awasthi, S., Sharma, A., Rogers, L., Matlock, E. F., Van Lint, C., Karpova, T., McNally, J., and R. Harrod (2004). Nerve growth factor receptor-signaling induces histone acetyltransferase domain-dependent nuclear translocation of p300/CREB-binding protein-associated factor and hGCN5 acetyltransferases. J. Biol. Chem. 279:55667-55674

R. Harrod, Nacsa, J., Van Lint, C., Hansen, J., Karpova, T., McNally, J., and G. Franchini (2003). HIV-1 Tat/co-activator acetyltransferase interactions Inhibit p53K320-acetylation and p53-responsive transcription. J. Biol. Chem. 278:12310-12318

Z. Hel, Johnson, J. M., Tryniszewska, E., Tsai, W. P., Harrod, R., Fullen, J., Tartaglia, J., and G. Franchini (2002). A novel chimeric Rev, Tat, and Nef antigen as a component of an SIV/HIV vaccine. Vaccine 20:3171-3186

Z. Hel., Tryniszewska, E., Tsai, W. P., Johnson, J. M., Harrod, R., Fullen, J., Kalyanaraman, V. S., Altman, J. D., McNally, J., Karpova, T., Felber, B. K., Tartaglia, J., and G. Franchini (2002). Design and in vivo immunogenicity of a polyvalent vaccine based on SIVmac regulatory genes. DNA and Cell Biol. 21:619-626

J. M. Johnson, Harrod, R., and G. Franchini (2001). Molecular biology and pathogenesis of the human T-cell leukaemia/lymphotropic virus type-1 (HTLV-1). Int. J. Exp. Path. 82: 135-147

C. Nicot and R. Harrod (2000). Distinct p300-responsive mechanisms promote caspase-dependent apoptosis by HTLV-1 Tax. Mol. Cell. Biol. 20:8580-8589

R. Harrod, Kuo, Y. L., Tang, Y., Yao, Y., Vassilev, A., Nakatani, Y., and C. Z. Giam (2000). p300 and P/CAF interact with HTLV-1 Tax in a multi-HAT/activator-enhancer complex. J. Biol. Chem. 275: 11852-11857

Y. L. Kuo, Tang, Y., Harrod, R., Cai, P., and C. Z. Giam (2000). Kinase-inducible domain-like region of HTLV type 1 Tax is important for NF-kappaB activation. AIDS Research and Human Retroviruses 16:1607-1612

Y. Yao, Kuo, Y. L., Wang, L. C., Harrod R., Tang, Y., Cai, P., Harrington, W. J., Boros, I., Shih, H. M., and C. Z. Giam (2000). Mechanisms of action of HTLV-1 Tax. Leukemia 14:535

R. Harrod, Tang, Y., Nicot, C., Lu, H. S., Vassilev, A., Nakatani, Y., and C. Z. Giam (1998). An exposed KID-like domain in HTLV-1 Tax is responsible for the recruitment of co-activators CBP/p300. Mol. Cell. Biol. 18:5052-5061

Y. Tang, Tie, F., Boros, I., Harrod, R., Glover, M., and C. Z. Giam (1998). An extended alpha-helix and specific amino acid residues opposite the DNA binding surface of the CREB basic domain are important for HTLV-1 Tax binding. J. Biol. Chem. 273:27339-27346

R. Harrod and P. S. Lovett (1997). Leader peptides of inducible chloramphenicol resistance genes from Gram-positive and Gram-negative bacteria bind to yeast and Archaea large subunit rRNA. Nucl. Acids Res. 25:1720-1726

R. Harrod and P. S. Lovett (1995). Peptide inhibitors of peptidyl transferase alter the conformation of domains IV and V of large subunit rRNA: A model for nascent peptide control of translation. Proc. Nat'l. Acad. Sci., USA 92:8650-8654

Z. Gu, Harrod, R., Rogers, E. J., and P. S. Lovett (1994). Properties of a pentapeptide inhibitor of peptidyltransferase that is essential for cat gene regulation by translation attenuation. J. Bacteriol. 176:6238-6244

Z. Gu, Harrod, R., Rogers, E. J., and P. S. Lovett (1994). Anti-peptidyl transferase leader peptides of attenuation-regulated chloramphenicol-resistance genes. Proc. Nat'l. Acad. Sci., USA 91:5612-5616

R. Harrod, Gu, Z., and P. S. Lovett (1994). Analysis of the secondary structure that negatively regulates inducible cat translation by use of chemical probing and mutagenesis. Gene 140:79-83

Support

Southwest Consortium for Anti-Infectives and Virological Research
(PI: R. Harrod)
Current

Role of HTLV-1 p30(II) in Adult T-cell Leukemogenesis (1R01CA127623-01A2). National Cancer Institute/National Institutes of Health
(PI: R. Harrod)
Pending

Membership in Professional Societies

American Society for Biochemistry and Molecular Biology (ASBMB)
Federation of American Societies for Experimental Biology (FASEB)
American Society for Microbiology (ASM)
New York Academy of Sciences (NYAS)
American Association for the Advancement of Science (AAAS)