Departments & Divisions
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.
Funding Agency NIH Title Proteasome function during aging in extraordinarily long-lived naked mole-rats Status Complete Period 9/2013 - 5/2016 Role Principal Investigator Grant Detail The primary goal is to characterize proteasome function and its role in aging in naked mole-rats.
Funding Agency San Antonio Area Foundation Title Toward optimization of the p[romising anti-cancer drug lead: elucidating molecular mechanism of drug-target binding by nuclear magnetic resonance spectroscopy Status Complete Period 3/2016 - 8/2017 Role Principal Investigator Grant Detail Funding Agency William and Ella Owens Medical Research Foundation Title Development of novel anti-cancer compounds targeting dimerization of proteasome with its regulatory modules. Status Complete Period 1/2016 - 12/2016 Role Principal Investigator Grant Detail
Funding Agency President?s Translational and Entrepreneurial Fund (PTEF) Title Targeting proteasomes to treat cancer. Status Complete Period 11/2015 - 8/2016 Role Co-Principal Investigator Grant Detail
Mahalingam, D., Osmulski, P., Wang, C-M., Horning, A.M., Louie, A.D., Lin, C-L., Gaczynska, M.E., Chen, C-L. SINGLE-CELL MOLECULAR PROFILES AND BIOPHYSICAL ASSESSMENT OF CIRCULATING TUMOR CELLS. In: Z. Hugh Fan. Circulating Tumor Cells: Isolation and Analysis. 2016. p. 329-351.
Maria Gaczynska, Przemyslaw Karpowicz, Christine E. Stuart, Malgorzata G. Norton, Jeffrey H. Teckman, Ewa Marszal, Pawel A. Osmulski. AFM imaging reveals topographic diversity of wild type and Z variant polymers of human alpha1-proteinase inhibitor PLoS One 2016 Mar;. Karpowicz P, Osmulski PA, Witkowska J, Sikorska E, Gizynska M, Belczyk-Ciesielska A, Gaczynska ME, Jankowska E. Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein PLoS One 2015 Nov;10(11):0143038-0143038. Rodriguez, K. A., Osmulski PA, Pierce AP, Weintraub, S. T., Gaczynska ME, Buffenstein R. A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition Biochim et Biophysi Acta 2014 Nov;:2060-2072. Osmulski, P.A., Mahalingam, D., Gaczynska, M., Liu, J., Huang, S., Horning, A.M., Wang, C-M., Thompson, I.M., Huang, T. H-M., Chen,. C-L. Nanomechanical biomarkers of single circulating tumor cells for detection of castration resistant prostate cancer Prostate 2014 Jan;74:1297-1307. Witkowska, J., Karpowicz, P., Gaczynska, M., Osmulski, P.A., Jankowska, E. Dissecting a role of a charge and conformation of Tat2 peptide in allosteric regulation of 20S proteasome Journal of Peptide Science 2014 Jan;psc(2642). Edrey, YH, Medina, DX, Gaczynska ME, 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):2352-2360. Osmulski PA, Gaczynska M. Rapamycin allosterically inhibits the proteasome Mol Pharmacol 2013 Jul;84(1):104-113. 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):813-826.
Gaczynska M, Osmulski PA, Gaczynska ME. Targeting Protein-Protein Interactions in the Proteasome Super-Assemblies Curr Top Med Chem 2015 Jan;15(20):2056-2067. Gaczynska M, Osmulski PA. Harnessing proteasome dynamics and allostery in drug design Antioxid Redox Signal 2014 Dec;21(17):2286-2301.