Department of biochemistry and Molecular biology
1975 Ph.D., University of Wisconsin, Madison, Wisconsin
1969 M.S., Vanderbilt University, Nashville, Tennessee
1967 B.S., Marietta College, Marietta, Ohio
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.
Recent Publications | Additional Publications
1. Joseph K, Spicer EK, Tholanikunnel BG. Regulatory mechanism of G protein-coupled receptor trafficking to the plasma membrane: a role for mRNA localization. Methods Enzymol. 2013;521:131-50. PMID: 23351737.
2. Subramaniam K, Kandasamy K, Joseph K, Spicer EK, Tholanikunnel BG. The 3'-untranslated region length and AU-rich RNA location modulate RNA-protein interaction and translational control of β2-adrenergic receptor mRNA. Mol Cell Biochem. 2011 Jun;352(1-2):125-41. Epub 2011 Mar 3. PMID: 21369731.
3. Ishimaru D, Zuraw L, Ramalingam S, Sengupta TK, Bandyopadhyay S, Reuben A, Fernandes DJ, Spicer EK. Mechanism of regulation of Bcl-2 mRNA by nucleolin and A+U rich element binding factor 1 (AUF1). J Biol Chem. 2010 Jun 22. [Epub ahead of print] PubMed PMID: 20571027.
4. 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. 2009 Dec 11;394(4):789-803. Epub 2009 Oct 2. PubMed PMID: 19800890; PubMed Central PMCID: PMC2789664.
5. Ishimaru D, Ramalingam S, Sengupta TK, Bandyopadhyay S, Dellis S, Tholanikunnel BG, Fernandes DJ, Spicer EK. Regulation of Bcl-2 expression by HuR in HL60 leukemia cells and A431 carcinoma cells. Mol Cancer Res. 2009 Aug;7(8):1354-66. Epub 2009 Aug 11. PubMed PMID: 19671677.
6. 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. 2009 Nov;76(5):984-91. Epub 2009 Aug 5. PubMed PMID: 19657047; PubMed Central PMCID:PMC2774992.
7. Soundararajan S, Chen W, Spicer EK, Courtenay-Luck N, Fernandes DJ. The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. Cancer Res. 2008 Apr 1;68(7):2358-65. PubMed PMID: 18381443.
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