Dr. Maria Gaczynska's lab is devoted to study large protein assemblies with chemical biology and biophysics methods. One of our major subjects of interest is the proteasome, a multifunctional macromolecular assembly essential in cell cycle progression, signal transduction pathways, immune response and general "housekeeping" in the human cell.
Not surprisingly, the proteasome is involved in cellular aging processes and in countless pathologies, including cancer and Alzheimer's disease. The proteasome is currently in the center of attention of clinicians and pharmacologists as a surprisingly promising drug target against cancer and inflammation. One of our goals is to provide an insight into the differences between structure and function of proteasomes in normal and neoplastically transformed cells and in cells in aging tissues. We propose that proteasome, together with other proteases that take a part in the controlled degradation of regulatory proteins in the cell, constitute a functional entity.
They form multibranched degradation pathways enabling a tight control of this irreversible process. We postulate that this web of interactions is dysfunctional in cancer or in aged organisms, creating a "proteolytic instability". Dissecting the web of interaction and aiming at its most vulnerable points would enable to manipulate the activities of the involved proteases to specifically kill tumor cells or to improve an immune response in aging tissue. Moving from metabolic pathways to the level of proteasome molecules, we concentrate on allosteric regulation of the enzyme's activity, using "nanoenzymology" methods ranging from atomic force microscopy to molecular modeling to small-molecule chemistry. We created a series of peptide and peptidomimetic compounds allosterically affecting the proteasome activities. We postulate that allosteric regulators will constitute perfect drugs precisely adjusting the proteasome actions for the benefit of the whole organism.
Chen CL, Mahalingam D, Osmulski P, Jadhav RR, Wang CM, Leach RJ, Chang
TC, Weitman SD, Kumar AP, Sun L, Gaczynska ME, Thompson IM, Huang TH. Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer. Prostate. 2013 Jun;73(8):813-26.
Osmulski PA, Gaczynska M. Rapamycin allosterically inhibits the proteasome. Mol Pharmacol. 2013 Jul;84(1):104-13.
Edrey YH, Medina DX, Gaczynska M, Osmulski PA, Oddo S, Caccamo A, Buffenstein R. Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease. Neurobiol Aging. 2013 Oct;34(10):2352-60.
Jankowska E, Stoj J, Karpowicz P, Osmulski PA, Gaczynska M. The proteasome in health and disease. Curr Pharm Des. 2013;19(6):1010-28.
Rodriguez KA, Edrey YH, Osmulski P, Gaczynska M, Buffenstein R. Altered composition of liver proteasome assemblies contributes to enhanced proteasome activity in the exceptionally long-lived naked mole-rat. PLoS One. 2012;7(5):e35890.