BBS Faculty Member - Shobha Vasudevan

Shobha Vasudevan

Department of Medicine

MGH Cancer Center
Richard B Simches Research Center
185 Cambridge Street, CPZN 4202/4100
Boston, MA 02114
Tel: 617-643-3143
Fax: 617-643-3170
Email: vasudevan.shobha@mgh.harvard.edu
Lab Members: 2 postdoctoral fellows, 2 technicians
Visit my lab page here.



AU-rich elements (AREs) are highly conserved mRNA 3’ untranslated region (UTR) regulatory elements while microRNAs are small non-coding RNAs that target distinct 3’UTR sites and control post-transcriptional gene expression of clinically relevant messages, including those of cytokines and potent growth factors. Recent evidences implicate microRNAs in ARE-mediated post-transcriptional regulation. MicroRNAs, like AREs, are known post-transcriptional regulators in cell proliferation, development and death; their deregulation lead to rapid and dramatic changes in expression levels promoting a broad range of critical effects, in particular, tumor growth and metastasis, several types of leukemias, lymphomas and developmental disorders.

Goal: The primary goal of our research program is to investigate microRNA- and other non-coding RNA-controlled regulation of expression of cancer associated genes; in particular, of clinically relevant ARE-bearing cytokine and growth factor mRNAs such as TNF
a, IL1β and VEGF that lead to tumor progression and metastasis. The focus of our research is to understand the underlying mechanisms of post-transcriptional regulation by microRNAs and their synergisms with AREs in tumor cells. An interconnected direction of our research is to investigate microRNP regulation by distinct cell states, in particular, by the cell cycle, hypoxia and in naturally quiescent side populations and germ cells.

Tumors promote cells that could adapt to unfavorable environments by entering quiescence, a reversible state to escape irreversible arrest or apoptosis that would be the usual outcome of tumor negative conditions. Quiescence involves gene expression reprogramming, upregulating those required for survival as well as specific microRNAs. The key finding of our studies on cytokine and growth factor gene expression, which forms the basis of our research program, is that AREs, microRNAs and microRNPs are transformed by such cellular conditions to alter expression patterns of specific, clinically important genes. We further identified in vivo post-transcriptional effectors associated with the mRNA under distinct conditions by developing an in vivo crosslinking coupled affinity purification method to purify endogenous RNP complexes. These findings opened a novel, unexplored area of research into the collaborative control over gene expression by two highly potent 3’UTR regulators, AREs and microRNAs, which have major implications for the expression of cytokines and growth factors that lead to tumor progression and metastasis.

There are four core directions:
1. To functionally characterize small non-coding regulatory RNAs, their associated cofactors and target mRNAs that encode for clinically important cytokines, cancer and cell state regulators using previously developed in vivo crosslinking coupled affinity purification methods and confirmatory assays
2. To investigate the mechanism of gene expression control and interconnections of the above identified small RNA regulators, AREs and microRNA target sites
3. To elucidate the regulation of expression and function of microRNAs and AREs by specific cellular conditions
4. To characterize the selective interactions between regulatory small RNAs and their mRNA targets in order to develop antisense manipulations of these interactions as specific therapeutic approaches.

These studies should lead to a greater understanding of the versatile role of regulatory small noncoding RNAs in the pathogenesis of cancers and to novel approaches in RNA-based therapeutic applications.



Last Update: 8/22/2013



Publications

LeTonqueze, O., Lee JH. and Vasudevan, S. (2012). Alternative microRNA-mediated post-transcriptional mechanisms of gene expression in proliferating and quiescent cancer cells. RNA Biology; 9 (6):871-880

An-Jou Chen, Ji-Hye Paik, Hailei Zhang, Sachet A. Shukla, Richard Mortensen, Jian Hu, Haoqiang Ying, Baoli Hu, Jessica Hurt, Natalie Farny, Caroline Dong, Yonghong Xiao, Yaoqi Alan Wang, Pamela A. Silver, Lynda Chin,
Shobha Vasudevan, and Ronald A. DePinho. (2012). Star RNA-binding protein, Quaking, suppresses cancer via stabilization of specific miRNA. Genes Dev.;26(13):1459-72.

Mortensen, R.D., Serra, M., Steitz, J.A. and
Vasudevan, S. (2011). Posttranscriptional activation of gene expression in Xenopus laevis oocytes by microRNA-protein complexes (microRNPs). PNAS, 108 (20) 8281-8286.

Vasudevan, S., Tong, Y. and Steitz, J.A. (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science. 318: 1931-1934.

Vasudevan, S., and Steitz, J.A. (2007). AU-rich element-mediated upregulation of translation by FXR1 and Argonaute2. Cell. 128: 1105-1118.

Vasudevan, S., Seli, E., and Steitz, J.A. (2006) Metazoan oocyte and early embryo development program: A progression through translation regulatory cascades. Genes Dev. 20 (2): 138-146.



© 2013 by the President and Fellows of Harvard College