Viswanathan Palanisamy PhD
Project : Title: Regulation of mRNA Stability in Oral Cancer
Our laboratory is interested in basic and translational research program to study post-transcriptional gene regulation during oral cancer development and progression. The major focus of our laboratory is to analyze the contribution of an unusual form of post-transcriptional gene expression, to mRNA metabolism and the adaptation of mRNA stability and their associated proteins to this process.
Our research hypothesis builds on the discoveries made over the past 3 years with a focus on cellular and molecular mechanisms of RNA binding proteins in oral cancer and to translate these findings into clinical applications, including development of biological markers for the diagnosis of oral cancer and exploring potential therapies designed to favorably modify the progression of the disease. The mRNA binding proteins especially HuR protein influences key aspects of mRNA metabolism including nuclear transit, export to the cytoplasm, cytoplasmic transport, storage, translation and turnover. Among various RNA-binding proteins HuR is among the most prominent protein influencing the cellular response to stress, proliferative signals, immune triggers and developmental cues. HuR encodes many proliferation-related mRNAs including cyclins, growth factors and transcription factors, which are the downstream targets to be studied in our laboratory. Given HuR’s influence on the expression of these key modulators, there must be a greatest interest in studying the HuR protein binding mRNAs and how they are regulated under the inhibitory and/or knock down conditions in oral cancer. Hence, our major focus is to decipher how protein HuR influences the gene expression of oral cancer utilizing the mRNA decay machinery. In total, this research will opens up the unstudied aspects of mRNA stability in normal and oral cancer and will lead to advances in therapeutic interventions.
Stabilization and destabilization of mRNA plays an important role in the regulation of gene expression. Our knowledge of presence of human mRNA and the stabilization that enables its presence in human saliva is very poor. The existence of viral, bacterial and human RNAs in saliva allows us to study the mechanisms and regulations of mRNA stability for various diseases. The challenges related to regulation of mRNA stability in human saliva, and how mRNA is stabilized by utilizing mRNA stability pathways is yet to uncover. We hypothesize that there are sequence elements and protein factors responsible for the differential presence of disease specific RNA biomarkers in saliva or oral cancer patients. This research will allow us to gain insights into the sequence elements and protein factors responsible for mRNA stability in human saliva. Therefore, the major goal of this project is to understand the mechanistic aspects of mRNA stability in human saliva. Two specific aims are proposed to accomplish these goals. I) Determine the fundamental mechanisms responsible for the stabilization of mRNA’s in human saliva and II) Validate the AU-rich element containing mRNA decay in correlation with MAP kinase pathway activation.
Viswanathan Palanisamy *, Shivani Sharma, Amit Deshpande, Hui Zhou, James Gimzewski, and David T. Wong. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS One, 5(1): e8577,(2010). * Corresponding author
Palanisamy V, Park NJ, Wang J, Wong DT: AUF1 and HuR proteins stabilize interleukin-8 mRNA in human saliva. J Dent Res. Aug;87(8):772-6. (2008)
Park, N J, Zhou, X, Yu, T, Brinkman, A B, Zimmermann, B G, Palanisamy, V, and Wong, D T: Assessing Salivary mRNA Integrity by cDNA Library Analysis. Arch Oral Biol.,52(1):30-5. (2006)
Viswanathan Palaniswamy, Karen C M Moraes, Carol J Wilusz & Jeffrey Wilusz: Nucleophosmin is selectively deposited on the mRNA during polyadenylation. Nature Structural and Molecular Biology, 13, 429 - 435 (2006)
Palaniswamy Viswanathan, Takbum Ohn, Yueh-chin Chiang, Junji Chen, and Clyde L. Denis.Mouse CAF1 can function as a processive deadenylase/3'- 5' exonuclease in vitro but in yeast the deadenylase function of CAF1 is not required for mRNA poly (A) removal. Journal of Biological Chemistry 279: 23988 - 23995. (2004)
Lisa B. Clark, Palaniswamy Viswanathan* Gloria Quigley, Yueh-Chin Chiang, Jeffrey S. McMahon, Gang Yao, Junji Chen, Andreas Nelsbach, and Clyde L. Denis. Systematic mutagenesis of the leucine-rich repeat (LRR) domain of CCR4 reveals specific sites for binding to CAF1 and a separate critical role for the LRR in CCR4 deadenylase activity. Journal of Biological Chemistry 2;279 (14): 13616-23 (2004)* Equally Contributed
Palaniswamy Viswanathan, Chen J, Chiang YC, Denis CL. Identification of multiple RNA features that influence CCR4 deadenylation activity. Journal of Biological Chemistry 278:14949-14955. (2003)