Research Interests

Micro-RNAs (miRNAs) are tissue-specific regulatory RNA molecules that silence gene expression post-transcriptionally. Specific miRNAs have been associated with tumor invasiveness, metastasis and other clinical characteristics of several cancers, including hepatocellular carcinomas (HCC). We developed a primary human hepatocyte cell culture model which is susceptible to infection with native HCV and allows an examination of authentic host response to HCV replication. Propagation of native virus strains in vitro allows a controlled system to study miRNAs and miRNA-regulated genes in response to viral stress. Specifically our studies are designed to ask how miRNAs induced by HCV target tumor suppressor genes (TSGs) that are commonly deleted in HCC, and thus provide a mechanistic trigger for the initiation of hepatocarcinogenesis. I have a relatively small group, one post-doc and two graduate students, engaged in studying the cell and molecular biological aspects of miRNA-targeted suppression of TSGs during viral stress and the initiation of human liver cancer. The web site will be periodically updated with recent publications.

Selected Publications

• Kumar A, Pederson T. Comparison of Proteins Bound to Heterogenous Nuclear RNA and Messenger RNA in Hela Cells. J. Mol. Biol. 96: 353-365, 1975.
  Primary transcripts within the nucleus, the so called hetreogenous nuclear (hnRNA) include the precursors of messenger RNA (pre-mRNAs). It was unclear whether the processing of pre-mRNAs into functional mRNA required association of specific proteins. This paper compared the protein composition of hnRNAs and mRNAs to understand the role proteins in the processing of primary transcripts in human cells.
• Irwin D, Kumar A, Malt RA. Messenger Ribonucleoprotein Complexes Isolated with Oligo (dt)-Cellulose Chromatography from Kidney Polysomes. Cell 4: 157-165, 1975.
  Understanding the functional significance of proteins associated with the messenger RNAs required affinity fractionation of mRNA-bound proteins. This paper described the first purification of a procedure for mRNA-protein complexes based on specific polyadenylate 3’ termini of messenger RNAs.
• Kumar A, Bandman E, Melvin WT. Ribosome Metabolism in Temperature-sensitive Mutant of BHK Cells. Nature 259: 692-694. 1976.
  Functional analysis of rRNA-protein interaction at this stage required that we extend our studies in a genetic model. We examined a conditional lethal mutant of ribosome biogenesis, where the assembly of large ribosomal subunit is blocked at the non-permissive temperature. This paper demonstrated the parameters of ribosome metabolism in human cells using the first genetic system in mammalian cells.
• Ouellette AJ, Bandman E, Kumar A. Ribosomal RNA Methylation in a Temperature-sensitive Mutant of BHK Cells. Nature 262:619-621, 1976.
  Post-transcriptional modification of RNAs, such as the 2’Omethylation of ribosomal RNA is an essential aspect of functionally competent ribosomes. This paper takes advantage of the first conditional mutant of mammalian ribosome to demonstrate the significance of RNA methylation in ribosome biogenesis.
• Jeang K-T, Shank PR, Kumar A. Transcriptional Activation of Homologous Viral Long Terminal Repeats by the Human Immunodeficiency Virus Type 1 or the Human T-cell Leukemia Virus Type 1 Tat Protein Occurs in the Absence of de novo Protein Synthesis. Proc. Natl. Acad. Sci. USA 85: 8291-8295, 1988.
  TAR RNA is a stem-loop structure within the 5’-non-coding region of HIV-1. We examined its role in RNA-Protein interaction and HIV-1 gene activation. In this paper we demonstrated that HIV-1 gene activation required the interaction of the TAR RNA hairpin structure and the viral Tat protein, independent of concomitant protein synthesis. This was equally true in related HTLV-1 gene expression.
• Zhou, M., Deng, L., Kashanchi, F., Shatkin, A.J., and Kumar, A. The Tat/TAR-dependent phosphorylation of RNAP II CTD stimulates co-transcriptional capping of HIV-1 mRNA. Proc. Natl. Acad.Sci.USA. 100:12666-12671, 2003.
  One of the important functions of the TAR RNA binding protein is its unique Tat-dependent kinase activity to phosphorylate the RNA polymerase II large subunit at Serine 2 and Serine 5 residues. This paper showed the functional significance of HIV-1 Tat-TAR RNA dependent activation of viral RNA capping, which likely makes the viral transcripts more stable.
• Kumar A. The silent defense: Micro-RNA directed defense against HIV-1 replication. Retrovirology, April 12; 4(1):26, 2007.
  Among the non-coding RNAs, the miRNA in human cells constitute the endogenous regulatory molecules that modulate gene expression both post-transcriptionally and at the transcription level. In this commentary, I discuss the role of RNA-mediated gene silencing as one of the principal mechanisms of innate antiviral response.