Donna L. George, Ph.D.

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Emeritus Associate Professor of Genetics
Associate Dean for Masters Programs, University of Pennsylvania School of Medicine
Department: Genetics

Contact information
526 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-898-5032
B.A. (Biology)
Wilkes College, Wilkes-Barre, Pennsylvania, Summa Cum Laude, 1969.
Ph.D. (Zoology, Genetics)
Rutgers University, New Brunswick, New Jersey, 1974.
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Description of Research Expertise

Research Interests
Our research interests are focused broadly on the molecular pathways governing cellular growth control and their disruption during the initiation and progression of human cancers.

Key words: cancer, apoptosis, autophagy, p53, hsp70, stress-response

Description of Research
Currently, one focus of investigation centers on the role of the p53 tumor suppressor gene in mediating programmed cell death (apoptosis). This gene governs a major pathway protecting human cells from malignant transformation, and it represents the most frequently mutated gene in human cancer. It is generally accepted that disruption of p53's apoptosis function directly contributes to tumor progression. Thus, understanding the mechanisms by which p53 acts in the execution of cell death pathways is of considerable importance in cancer biology. Clearly established is p53's role as a nuclear transcription factor with the ability to activate, or repress, the expression of many genes. Accumulating data, however, now reveal that p53 has a direct cytoplasmic role at mitochondria in activating the apoptotic machinery. We have obtained several key pieces of evidence supporting this conclusion. Ongoing efforts are aimed at defining the overall contribution of this non-canonical role of p53 to apoptosis induction, and identifying other cellular factors that help to regulate this pathway. As part of these efforts, we are identifying mitochondrial p53-interacting proteins. Utilizing affinity chromatography and mass spectrometry, for example, we uncovered an interaction between p53 and the mitochondrial protein BAK. BAK is a critical "gatekeeper" of mitochondrial integrity and regulator of cellular cell death pathways. When p53 binds to BAK, it triggers a conformational change in BAK, leading to BAK oligomerization. This, in turn, activates the mitochondrial apoptosis pathway. These data support the importance of BAK as a mediator of p53's mitochondrial function. Ongoing studies are aimed at identifying and characterizing other critical cellular factors that act to inhibit or promote p53-mediated apoptosis, including its role at mitochondria.

Another major focus of our research centers on the multifunctional, stress-inducible, molecular chaperone called HSP70. This protein has a key cytoprotective role in a broad range of activities that promote protein homeostasis, including the targeting of potentially toxic proteins for proteolysis. Cancer cells experience high levels of protein-modifying- and metabolic-stresses and seem to be particularly dependent on the various actions of HSP70 for survival. This phenomenon, referred to as "non-oncogene addiction", suggests that it may be possible to target such critical survival proteins for the development of therapies aimed at the selective killing of neoplastic cells. We have recently identified a small molecule that interacts selectively with HSP70, and leads to a disruption of the association between HSP70 and several of its co-chaperones and substrate proteins, including p53. Treatment of cultured tumor cells with this drug promotes cell death that is associated with protein aggregation, impaired autophagy, and inhibition of lysosomal function. Moreover, this small molecule is able to suppress tumor development and enhance survival in a mouse model of lymphomagenesis. Thus the discovery of this new reagent represents a valuable tool to advance basic investigations on the varied activities of the HSP70 protein, and also should have application in the development of effective therapies aimed at simultaneously disabling multiple cancer-critical biological processes. Together with other lines of investigation, these studies promise to provide new insight concerning critical determinants of growth control in normal and transformed cells and have implications for cancer treatment.

Selected Publications

Leu, JI, Murphy ME, George DL: Targeting ErbB3 and Cellular NADPH/NADP+ Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers. ACS Chem. Biol. 17: 1038-1044, 2022.

Leu JI, Murphy ME, George DL: P53 regulates cellular redox state, ferroptosis and metabolism. Mol Cell Oncol 8(2): 1877076, 2021.

Parris, J. L. D.; Barnoud, T.; Leu, J. I.; Leung, J. C.; Ma, W.; Kirven, N. A.; Poli, A. N. R.; Kossenkov, A. V.; Liu, Q.; Salvino, J. M.; George, D. L.; Weeraratna, A. T.; Chen, Q.; Murphy, M. E.: HSP70 Inhibition Blocks Adaptive Resistance and Synergizes with MEK Inhibition for the Treatment of NRAS-Mutant Melanoma. Cancer Research Communications 1(1): 17-29, 2021.

Leu JI, Murphy ME, George DL: Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of TP53. Proc. Natl. Acad. Sci. USA 117(43): 26804-26811, 2020.

Gnanapradeepan K, Leu JI, Basu S, Barnoud T, Good M, Lee JV, Quinn WJ, Kung CP, Ahima R, Baur JA, Wellen KE, Liu Q, Schug ZT, George DL, Murphy ME: Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser. Elife 9: e55994, 2020.

Singh, K.S., Leu, J.I., Barnoud, T., Vonteddu, P., Gnanapradeepan, K., Lin, C., Liu, Q., Barton, J.C., Kossenkov, A.V., George, D.L., Murphy, M.E., and Dotiwala, F.: An African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin. Nature Communications 11(1): 473, 2020.

Barnoud T, Leung JC, Leu JI, Basu S, Poli ANR, Parris JLD, Indeglia A, Martynyuk T, Good M, Gnanapradeepan K, Sanseviero E, Moeller R, Tang HY, Cassel J, Kossenkov AV, Liu Q, Speicher DW, Gabrilovich DI, Salvino JM, George DL, Murphy ME: A novel inhibitor of HSP70 induces mitochondrial toxicity and immune cell recruitment in tumors. Cancer Research 80(23): 5270-5281, 2020.

Leu JI, Murphy ME, George DL: Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc. Natl. Acad. Sci. USA 116(17): 8390-8396, 2019.

Barnoud T, Budina-Kolomets A, Basu S, Leu JI, Good M, Kung CP, Liu J, Liu Q, Villanueva J, Zhang R, George DL, Murphy ME: Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Research 78(19): 5694-5705, 2018.

Leu, J.I., Barnoud, T., Zhang, G., Tian, T., Wei, Z., Herlyn, M., Murphy, M.E. and George, D.L: Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function. Oncotarget 2017.

Jennis, M., Kung, C-P., Basu, S., Budina-Kolomets, A., Leu, J.I., Khaku, S., Scott, J.P., Cai, K.Q., Campbell, M.R., Porter, D.K., Wang, X., Bell, D.A., Li, X., Garlick, D.S., Liu, Q., Hollstein, M., George, D.L. and Murphy, M.E: An African-specific polymorphism in the p53 gene impairs p53 tumor suppressor function in a mouse model. Genes & Dev 30: 918-930, 2016.

Kung, C-P., Leu, J.I., Basu, S., Khaku, S., Anokye-Danso, F., Liu, Q., George, D.L., Ahima, R.S. and Murphy, M.E. : The P72R polymorphism of p53 predisposes to obesity and metabolic dysfunction. Cell Reports 14: 2413-2425, 2016.

Budina-Kolomets, A., Webster, M.R., Leu, J.I., Jennis, M., Krepler, C., Guerrino, A., Kossenkov, A., Xu, W., Karakousis, G., Shuchter, L., Amaravadi, R.K., Wu, H., Liu, Q., Liu, Y., Mills, G.B., Xu, X., George, D.L., Weeraratna, A.T. and Murphy, M.E: HSP70 inhibition limits FAK-dependent invasion and enhances the response to melanoma treatment with BRAF inhibitors. Cancer Res. 76: 2720-2730, 2016.

Zhang, P., Leu, J. I-Ju, Murphy, M.E., George, D.L. and Marmorstein, R.: Crystal structure of the stress- inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. PLoS One 9: e103518, 2014.

Balaburski, G.M., Leu, J. I-Ju, Beeharry, N., Hayik, S., Andrake, M.D., Zhang, G., Herlyn M.,Villanueva J., Dunbrack Jr. R., Yen, T., George, D.L. and Murphy, M.E. : A modified HSP70 inhibitor induces mitotic defects in tumor cells and shows significant pre-clinical efficacy in a murine model of lymphoma. Mol. Cancer Res. 11: 219-229, 2013.

Leu, J.I-Ju, Zhang, P., Murphy, M.E., Marmorstein, R. and George, D.L. : Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. ACS Chem. Biol 9: 2508-2516, 2014.

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Last updated: 05/23/2022
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