Andrew P. Rice, Ph.D.
Nancy Chang Professor
Department of Molecular Virology & Microbiology
Our general research interest is the regulation of gene expression during viral infection. Studies of viral gene regulation contribute to the understanding of important human pathogens and often lead to insight into general biological processes. During the past several years, we have largely focused on gene regulation during human immunodeficiency virus (HIV) infection. We have investigated the mechanism of action of the viral transcriptional activator protein known as Tat. Tat is unusual among transcriptional activator proteins in that it is targeted to cellular RNA polymerase II through binding to a promoter-proximal RNA element known as TAR, where it then acts to greatly stimulate transcriptional elongation of the integrated HIV provirus. We and others have obtained evidence that in order to activate transcription elongation, Tat targets the carboxyl terminal domain (CTD) of the largest subunit of RNA polymerase II for modification by phosphorylation. It is believed that CTD phosphorylation activates transcription by stimulating the promoter clearance of transcription complexes and/or converting elongation-deficient transcription complexes to highly processive complexes.
Several years ago, we identified a cellular serine/threonine protein kinase, now termed P-TEFb, which is the crucial co-factor that the Tat protein binds to, resulting in phosphorylation of the CTD and the subsequent activation of transcription of the viral genome. Core P-TEFb is composed of two subunits - Cdk9 is the catalytic subunit and Cyclin T1 is a regulatory subunit that makes protein-protein contact with Tat. Our current studies include further investigation of the molecular mechanisms involved in P-TEFb and Tat function. We are particularly interested in investigating the normal cellular roles and regulation of P-TEFb in cell types relevant to HIV infection, namely CD4+ T cells and monocytes/macrophages. We are hopeful that our future studies will contribute to the understanding of fundamental principles of gene regulation in both viral and cellular systems.
Given the laboratory’s long standing interest in host-cell interactions, we have become involved in an influenza A virus project. Highly virulent strains of H5N1 avian influenza viruses are currently circulating in birds in Asia, Europe, and Africa. The NS1 protein of avian viruses has been shown to be associated with virulence. An important feature of the avian NS1 protein is the presence of a four amino acid domain at its carboxyl terminus termed the PDZ Binding Motif (PBM). The PBM is predicted to associate with cellular PDZ proteins, a large class of proteins that are typically involved in cell-cell contact and cellular polarity. H5N1 viruses that have infected humans with an approximate 50% mortality rate encode an NS1 protein with a PBM with the consensus sequence ESEV. We have identified a number of PDZ cellular proteins that associate with the ESEV PBM: Dlg1, Scribble, MAGI-1, MAGI-2, and MAGI-3. Our current research is involved in determining the functional significance of the interaction of the NS1 ESEV PBM with these cellular proteins.
Department of Molecular Virology & Microbiology
Baylor College of Medicine
One Baylor Plaza, MS BCM385
Houston, TX, 77030, U.S.A.
Ph.D. - Brandeis University
Postdoctoral - Imperial Cancer Research Fund Laboratory, London
Awards, Appointments and Honors
Michael E. DeBakey Excellence in Research Award, 1998
Nancy Chang Professor of Molecular Virology and Microbiology, 2008
Fellow, American Academy of Microbiology (elected), 2010
Yu W., Ramakrishnan R., Wang Y., Chiang K., Sung T.-L., Rice A.P. (2008) Cyclin T1-Dependent Genes in Activated CD4+ T and Macrophage Cell Lines Appear Enriched in HIV-1 Co-Factors. PLoS ONE 3(9): e3146.
Wang, Y., Dow, E.C., Liang, Y.-Y., Ramakrishnan, R., Lin X., Feng, X.-H., and Rice A.P. (2008). Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop. Journal of Biological Chemistry. 283: 33578-84. Epub Oct 1, 2008.
Sung, T-L and Rice, A.P. (2009). MicroRNA-198 inhibits HIV-1 gene expression and replication and its mechanism of action appears to involve repression of Cyclin T1 expression. PLoS Pathogens. E10000263. Epub2009 Jan16.
Yukl, S., Pillai, S., Li, P., Chang, K., Pasutti, W., Ahlgren, C., Havlir, D., Strain, M., Guenthard, H., Richman, D., Rice, A.P., Daar E., Little, S., and Wong, J.K. (2009). Latently-infected CD4+ T Cells are enriched for HIV-1 Tat variants with impaired transactivation activity. Virol. 387:98-108. Epub Mar 4, 2009.
Ramakrishnan, R., Dow, E.C. and Rice, A.P. (2009) Characterization of Cdk9 T-loop phosphorylation in resting and activated CD4+ T lymphocytes. J. Leuk. Biol. 86:1345-50. Epub Sept 9, 2009.
Dow, E.C., Liu, H. and Rice A.P. (2010) T-loop phosphorylated Cdk9 localizes to nuclear speckle domains which may serve as sites of active P-TEFb function and exchange between the Brd4 and 7SK/HEXIM regulatory complexes. J. Cell. Physiol. 224:84-93.
Liu, H., Herrmann, C.H., Chiang, K., Sung, T-L., Moon, S-H., Donehower, L.A., and Rice, A.P. (2010). 55K isoform of CDK9 associates with Ku70 and is involved in DNA repair. Biochem. Biophys. Res. Comm. 397:245-250. Epub May 20, 2010.
Liu, H., Golebiewski, L., Dow, E.C., Krug, R.M., Javier, R.T. and Rice A.P. (2010) The ESEV PDZ binding-motif of the avian influenza A virus NS1 protein protects infected cells from apoptosis through directly targeting Scribble. J. Virol. 84:11164-11174
Ramakrishnan, R. and Rice, A.P. (2011) Cdk9 T-loop phosphorylation is regulated by the calcium signaling pathway. J. Cel. Physiol. 2011 Mar 29. doi: 10.1002/jcp.22760. [Epub ahead of print].
Chiang, K. and Rice, A.P. 2011. Mini ways to stop a virus: microRNAs and HIV-1 replication. Future Virology 6:209-221.