Dictyostelium discoideum Studies

Using the model organism Dictyostelium discoideum to discover genes that function to determine sensitivity to drugs.

Dictyostelium discoideum is well known for its usefulness in studying the basic processes underlying multicellular development. Powerful molecular biological techniques including homologous recombination and random insertional mutagenesis, coupled with a fully sequenced genome, make this a very attractive system for study.

Using these same genetic approaches we have used D. discoideum as a lead genetic model to understand resistance to chemotherapeutic drugs. Libraries of insertional mutants have been constructed and subjected to selection for mutants that have increased resistance to drugs including cisplaitin. A number of mutants were discovered, the most notable of which was a disruption in the spingosine-1-phospahte lyase gene, which has now been extensively studied.

We continue to use the system for the isolation of mutants with resistance to other drugs as this strategy leads to the discovery of previously unknown biochemical pathways that regulate drug sensitivity.

Selected publications 

Williams, R.S., Boeckeler, K., Graf, R., Muller-Taubenberger, A., Li, Z., Isberg, R.R., Wessels, D., Soll, D.R., Alexander, H., and Alexander, S. (2006). Towards a molecular understanding of human diseases using Dictyostelium discoideum. Trends Mol Med 12: 415-424. Epub. August 4, 2006.

Alexander, S., Min, J., and Alexander, H. (2006). Dictyostelium discoideum to human cells: pharmacogenetic studies demonstrate a role for sphingolipids in chemoresistance. Biochim Biophys Acta 1760: 301-309. Epub. December 22, 2005.

Min, J., Traynor, D., Stegner, A.L., Zhang, L., Hanigan, M.H., Alexander, H., and Alexander, S. (2005a). Sphingosine kinase regulates the sensitivity of Dictyostelium discoideum cells to the anticancer drug cisplatin. Eukaryot Cell 4: 178-189.

Min, J., Traynor, D., Stegner, A.L., Zhang, L., Hanigan, M.H., Alexander, H., and Alexander, S. (2005a). Sphingosine kinase regulates the sensitivity of Dictyostelium discoideum cells to the anticancer drug cisplatin. Eukaryot Cell 4: 178-189.

Li, G., Foote, C., Alexander, S., and Alexander, H. (2001). Sphingosine-1-phosphate lyase has a central role in the development of Dictyostelium discoideum. Development 128: 3473-3483.

Li, G., Alexander, H., Schneider, N., and Alexander, S. (2000). Molecular basis for resistance to the anticancer drug cisplatin in Dictyostelium. Microbiology 146: 2219-2227. (FEATURED in Microbiology Today 27: 302 (2000))