Office: 843-792-7475
Lab: 843-792-1180
Fax: 843-792-8565
Email: spicer@musc.edu
BSB-512D

Research Interests

Regulation of mRNA stability of oncogenes, translational control of gene expression; protein:RNA interactions,
I. Post-transcriptional regulation of human bcl-2 expression
The molecular mechanisms that regulate apoptosis are not yet completely understood; however, multiple lines of evidence point to a role for Bcl-2 in regulating programmed cell death. In mammalian species, the Bcl-2 gene encodes a 29-kDa protein that predominantly resides in the outer mitochondrial membrane and nuclear envelope. Several studies have demonstrated that chemotherapeutic agents can alter Bcl-2 activity in a variety of cancer cells.  Based on our examination of the effects of taxol and okadaic acid on bcl-2 expression in the human leukemia cell line HL-60, we hypothesize that chemotherapeutic agents induce destabilization of bcl-2 mRNA by regulating the interactions of bcl-2 mRNA binding proteins with specific cis-elements in bcl-2 mRNA. Accordingly, our objectives are to identify the sequences or structures in bcl-2 mRNA that determine its sensitivity to chemotherapeutic agents such as taxol, and to identify and characterize the trans-acting factors that interact with these sequences.  Because of its anti-apoptotic activity, high Bcl-2 expression by malignant cells is potentially an obstacle to some forms of chemotherapeutic treatment. Our preliminary studies have shown that taxol-induced modulation of bcl-2 mRNA levels occurs via mRNA destabilization. This suggests that factors that influence bcl-2 mRNA stability may have significant therapeutic value. Currently, little is known about post-transcriptional regulation of bcl-2. Studies in our laboratory seek to address this deficiency in our knowledge and to provide new insights into this potentially important mechanism of controlling levels of the proto-oncoprotein Bcl-2.
II.  Regulation of nucleolin expression:

Cellular control of gene expression via mRNA stability is a relatively unexplored area of oncology. Studies in my laboratory are examining the post-transcriptional regulation of two genes that are associated with cancer pathogenesis, namely the proliferation associated protein nucleolin and the anti-apoptosis protein Bcl-2 (described above). We have found that nucleolin and bcl-2 protein are overexpressed in leukemia and breast cancer cells. Even though nucleolin is essential in normal cells, in cancer cells its elevated expression allows for increased proliferation and/or cell survival, in part due to upregulation of the expression of bcl-2. Although the aberrant expression and localization of nucleolin in cancer cells has profound consequences, the biochemical mechanisms leading to these events are not known. Our studies have demonstrated that bcl-2 upregulation in some cancer cells is due to stabilization of bcl-2 mRNA by nucleolin through interaction with elements in the 3 ’ untranslated region of the mRNA. Our recent studies suggest that nucleolin may upregulate its own expression in leukemia and breast cancer cells. Studies are in progress to determine if nucleolin expression is regulated post-transcriptionally and if nucleolin plays an autoregulatory role in the process in some cells.

Selected Publications

Click here to view list of publications on the National Library of Medicine's PubMed online database.

• Daniella Ishimaru, Lisa Zuraw, Sivakumar Ramalingam, Tapas K. Sengupta, Sumita Bandyopadhyay, Adrian Reuben, Daniel J. Fernandes and Spicer, EK, Mechanism of regulation of bcl-2 mRNA by nucleolin and AUF1, submitted, 2010
• Demarse, NA, Ponnusamy, S, Spicer, EK, Apohan, E, Baatz, JE, Ogretmen, B, Davies, C. Direct Binding of Glyceraldehyde 3-Phosphate Dehydrogenase to Telomeric DNA Protects Telomeres against Chemotherapy-Induced Rapid Degradation. J Mol Biol, 394, 789-803, 2009
• Soundararajan S, Wang, L, Sridharan, V, Chen W, Courtenay-Luck N, Jones, D, Spicer, EK, Fernandes DJ. Plasma membrane nucleolin is a receptor for the anticancer aptamer AS1411 in MV4-11 leukemia cells. Mol Pharmacol, 76, 984-991, 2009
• Ishimaru, D, Ramalingam, S, Sengupta, R, Bandyopadhyay, S, Dellis, S, Tholanikunnel,B, Fernandes, DJ and Spicer, EK. Regulation of Bcl-2 Expression by HuR in HL60 Leukemia Cells and A431 Carcinoma Cells. Molecular Cancer Res 9 (8), 1354 – 1366, 2009
• Soundararajan, S., Chen, W., Spicer, E.K., Courtenay-Luck, N. and Fernandes, D.J. “The nucleolin targeting aptamer As1411 destabilizes bcl-2 mRNA in human breast cancer cells”. Cancer Research, 68 (7) 2358-2365, 2008.
• Bandyopadhyay, S., Sengupta, T.K. and Spicer, E.K. “PMA induces stabilization of oncostatin M mRNA in human lymphoma U937 cells”. Biochem. J., 410, 177-186, 2008.
• Otake, Y., Soundararajan, S., Sengupta, T.K., Kio, E.A., Smith, J.C., Pineda-Roman, M., Stuart, R.K., Spicer, E.K. and Fernandes, D.J. “Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl-2 mRNA". Blood, 109: 3069-3075, (2007).
• Bose, S.K., Sengupta, T.K., Bandyopadhyay, S. and Spicer, E.K. “Identification of Ebp1 as a component of cytoplasmic bcl-2 mRNP complexes". Biochem. J., 396: 99-107, (2006)
• Otake, Y., Sengupta, T.K., Bandyopadhyay, S., Spicer, E.K., and Fernandes, D.J. (2005) Retinoid-Induced Apoptosis in HL-60 cells is Associated with Decreased Stabilization of bcl-2 mRNA by Nucleolin.  Molecular Pharmacology, 67, 319 -326
• Yang, W., White, B., Spicer, E.K., and Hildebrandt, J. (2004) Complex haplotype structure of the human GNAS gene identifies a recombination hot spot centered on a SNP associated with hypertension. Pharmacogenetics 14: 1-7.
• Otake, Y., Sengupta, T.K., Bandyopadhyay, S., Spicer, E.K. and Fernandes, D.J. (2004) Drug-induced destabilization of Bcl-2 mRNA: A new Approach for Inducing Apoptosis in Tumor Cells.  Current Opinions in Investigational Drugs 5(6): 616-622.
• Sengupta, T.K,., Bandyopadhyay, S., Fernandes, D. and Spicer, E.K. (2004) Identification of nucleolin as an AU-rich element binding protein involved in Bcl-2 mRNA stabilization. J. Biological Chemistry 279: 10855-10863.
• Bandyopadhyay, S., Sengupta, T.K., Fernandes, D. and Spicer, E.K. (2003) Taxol- and okadaic acid-induced destabilization of bcl-2 mRNA is associated with decreased binding of proteins to a bcl-2 instability element. Biochemical Pharmacology, 66: 1151-1162.
• Ullian, M.E., Gantt, B.J., Ford, A.K., Tholanikunnel, B.G., Spicer, E.K. and Fitzgibbon, W.R. (2003) Potential importance of glomerular citrate synthase activity in remant nephropathy. Kidney Int., 63(1): 156-164.
• Sengupta, T.K., Gordon, J., and Spicer, E.K. (2001) RegA proteins from phage T4 and RB69 have conserved helix-loop groove RNA binding motifs but different RNA binding specificities. Nucleic Acids Research, 29(5): 1175-1184.
• Gordon, J., Sengupta, T.K., Phillips, C.A., O'Malley, S.M., Williams, K.R., and Spicer, E.K. (1999) Identification of the RNA Binding Domain of T4 RegA Protein by Structure-based Mutagenesis. J. Biological Chemistry 274(45): 32265-32273.
• Goodrich, L.D., Lin, T-C., Spicer, E.K., Jones, C., and Konigsber, W.J. (1997) Residues at the carboxy terminus of T4 DNA polymerase are important determinants for interaction with the polymerase accessory proteins. Biochemistry 36(34): 10474-10481.
• Narasimhan, S., Armstrong, M., McClung, J.K., Richards, F.R., and Spicer, E.K. (1997) Prohibitin, a putative negative control element present in Pneumocystis carinii. J. Infection and Immunity 65(12): 5125-5130.
• Phillips, C.A., Gordon, J., and Spicer, E.K. (1996) Bacteriophage T4 regA protein binds RNA as a monomer, overcoming dimer interactions. Nucleic Acids Research 24: 4319-4326.