Untitled Document

Research

James S. Malter

M.D., Washington University, St. Louis
Professor, Department of Pathology
jsmalter@wisc.edu
http://www.pathology.wisc.edu/faculty/bio.aspx?name=jmalter

Post Transcriptional Gene Regulation

The main area of interest of my laboratory is to understand how mRNA stability and translation are controlled at both the cellular and molecular level. These two processes are critical for the regulated production of a variety of growth regulatory molecules, including proto-oncogenes, cytokines, some cell surface receptors and other critical proteins. A major benefit of regulation at a post transcriptional level is the rapidity with which a cell can up or down regulate a particular protein in response to changes in the environment.

The amyloid precursor protein (APP) is over-produced in Alzheimer's Disease (AD). APP is the precursor for Β-amyloid which accumulates in the extracellular space of AD brain, probably causing neuronal death. Similar morphology is observed in the brains of patients with trisomy 21 or Down syndrome. Many investigators currently believe that the over-production of Β-amyloid is a critical event leading to the development of AD.

Excess APP production may be caused by excess APP mRNA accumulation. Indeed, in multiple studies of AD or Down syndrome patients, APP mRNA levels are often elevated 1.5 to 2 fold. In the case of Down syndrome, the extra APP gene inherited by these individuals likely accounts for their excess APP mRNA levels. In AD patients, however, it remains unclear how APP mRNA levels are regulated. We have proposed that stabilization of APP mRNA could account for its accumulation in AD brain. Working from this hypothesis, we have characterized the decay of APP mRNA in resting and activated cells, as well as cycling tumor cells of neuronal lineage. Under resting conditions, APP mRNA is moderately stable with a half-life of approximately 4 hours. Cell activation or cell cycling increases the stability of APP mRNA to a half-life of >10 hours. We have identified 2 distinct regions of APP mRNA which control its stability. A 29 base region 200 bases downstream from the stop codon decreases, while a 52 base region adjacent to the stop codon increases, the stability of APP mRNA. These effects occur through interactions with sequence specific mRNA binding proteins.

We are presently evaluating the possibility of blocking APP and -amyloid production by interfering with the above mentioned 52 base stabilizing region by antisense oligonucleotides or the overexpression of decay mRNAs.

The dominant techniques employed in my laboratory include standard cell and molecular biology methods, protein biochemistry, molecular neuroscience and molecular genetics.

Representative Publications
Wang, D.-S., Dickson, D.W., & Malter, J.S. (2008). Tissue Transglutaminase, Protein Cross-Linking and Alzheimer's Disease: Review and Views. Int. J. Clin. Exp. Pathol., 1(1), 5-18.

Oleg Broytman, O., Westmark, P.R., Gurel, Z., & Malter, J.S. (2008). Rck/p54 interacts with APP mRNA as part of a multi-protein complex and enhances APP mRNA and protein expression in neuronal cell lines. Neurobiology of Aging, 2008 April 2 [Epub ahead of print].

Esnault, S., Braun, R.K., Shen, Z.J., Xiang, Z., Heninger, E., Love, R.B., Sandor, M., & Malter, J.S. (2007). Pin1 modulates the type 1 immune response. PLoS ONE, 21(2), e226.

Westmark, C.J., & Malter, J.S. (2007). FMRP mediates mGluR5-Dependent translation of Amyloid precursor protein. PLoS Biol., 5(3), e52.

Wang, S., Simon, B.P., Bennett, D.A., Schneider, J.A., Malter, J.S., & Wang, D.-S. (2007). The significance of Pin1 in the development of Alzheimer's disease. J. Alzheimer�s Dis., 11(1), 13-23.

Westmark, P.R., Shin, H.C., Westmark, C.J., Soltaninassab, S.R., Reinke, E.K., & Malter, J.S. (2006). Decoy mRNAs reduce beta-amyloid precursor protein mRNA in neuronal cells. Neurobiol. Aging, 27(6), 787-96.

Westmark, P.R., Shin, H.C., Westmark, C.J., Soltaninassab, S.R., Reinke, E.K., & Malter, J.S (2006). Decoy mRNAs reduce beta-amyloid precursor protein mRNA in neuronal cells. Neurobiol. Aging, 27(6), 787-96.

Esnault, S., Shen, Z.J., Whitesel, E., & Malter, J.S. (2006). The peptidyl-prolyl isomerase Pin1 regulates granulocyte-macrophage colony-stimulating factor mRNA stability in T lymphocytes. J. Immunol., 177(10), 6999-7006.

Shen, Z.J., Esnault, S., & Malter, J.S. (2005). The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat. Immunol., 6(12), 1280-7.

Esnault, S., & Malter, J.S. (2002). Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. Blood, 99(11), 4048-4052.

Westmark, C.J., & Malter, J.S. (2001). Extracellular-regulated kinase controls beta-amyloid precursor protein mRNA decay. Molecular Brain Research, 90(2), 193-201.

Westmark, C., & Malter, J.S. (2001). Regulation of Nucleolin mRNA and Protein by Multiple Signaling Pathways. J. Biol. Chem., 276(2), 1119-1126.

Capowski, E.E., Esnault, S., Bhattacharya, S., & Malter, J.S. (2001). Y box-binding factor promotes eosinophil survival by stabilizing granulocyte-macrophage colony-stimulating factor mRNA. Journal of Immunology. 167(10), 5970-5976.

Esnault, S., & Malter, J.S. (2001). Granulocyte macrophage-colony-stimulating factor mRNA is stabilized in airway eosinophils and peripheral blood eosinophils activated by TNF-alpha plus fibronectin. Journal of Immunology, 166(7), 4658-4663.

Rajagopolan, L., & Malter, J.S. (2000). Growth factor mediated stabilization of Amyloid Precursor Protein mRNA is mediated by a conserved 29-Nucleotide Sequence in the 3'UTR. J. Neurochem., 74, 52-59.

Ruth, J.H., Esnault, S., Jarzembowski, J.A., & Malter, J.S. (1999). Calcium ionophore upregulation of AUUUA-specific binding protein activity is contemporaneous with granulocyte macrophage colony-stimulating factor messenger RNA stabilization in AML14.3D10 cells. American Journal of Respiratory Cell & Molecular Biology, 21(5), 621-628.

Rajagopalan, L.E., Westmark, C.J., Jarzembowski, J.A., & Malter, J.S. (1998). hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic Acids Research, 26(14), 3418-3423.

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