Donna L. George
Associate Professor, Dept of Genetics

Genetics and Gene Regulation Program

Address

526 Clinical Research Building,
415 Curie Blvd.
Philadelphia, PA 19104

Office tel.: 215 898-5032
Lab tel.: 215 898-5033
Fax: 215 573-9411
E-mail: georged@mail.med.upenn.edu

Education

Wilkes University, B.A. (Biology) 1967

Rutgers University, Ph.D. (Genetics, Zoology) 1974

Oak Ridge National Laboratory; University of California, Postdoctoral research (Genetics, Gene Regulation)

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, tumorigenesis, apoptosis, p53, mdm2, gene regulation, stress-response.

Description of Research

Currently, a major 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' 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.

Interestingly, some tissues are very sensitive to apoptosis induced by p53, while others, such as liver, are quite resistant; however, the molecular basis for this difference remains poorly understood. In recent studies, we discovered that p53 activation in liver hepatocytes leads to enhanced expression of a liver-specific protein called IGFBP1 (insulin-like growth factor binding protein-1). Exhibiting a previously unanticipated role, a portion of intracellular IGFBP1 protein localizes to mitochondria where it binds to the proapoptotic protein BAK and hinders BAK activation and apoptosis induction. Notably, when IGFBP1 is in a complex with BAK, formation of a proapoptotic p53/BAK complex and apoptosis induction are impaired, both in cultured cells and in liver. In contrast, livers of IGFBP1-deficient mice exhibit spontaneous apoptosis that is accompanied by p53 mitochondrial accumulation and evidence of BAK-oligomerization. Our data support the importance of BAK as a mediator of p53's mitochondrial function. They also identify IGFBP1 as a negative regulator of the BAK-dependent pathway of apoptosis, whose expression integrates the transcriptional and mitochondrial functions of p53 in hepatic cells.

Future studies are aimed at identifying and characterizing those critical cellular factors that act to inhibit or promote p53-mediated apoptosis. These studies also have implications for better understanding autophagy, another important cell survival pathway that occurs in response to various forms of stress and is affected by p53 dysregulation. The goal of this work is to gain new information that may be utilized for the development of new strategies to combat cancers. Our studies, then, have implications for cancer diagnosis and therapy, and should provide new insight concerning critical determinants of growth control in normal and transformed cells.

Selected Publications

Leu, J.I. and George, D.L. : Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev. 21: 3095-3109, 2007.
Notes: Highlighted in a "Perspective" report: Guicciardi, M.E. and Gores, G.J., Science Signaling, 1:pe9, 2008 (PMID: 18285608).

Pietsch, E. C., Leu, J.I., Frank, A., Dumont, P., George, D.L. and Murphy, M.E: The tetramerization domain of p53 is required for efficient BAK oligomerization. Cancer Biol. Therapy 6(10): 1576-1583 2007.

Leu, J.I., Dumont, P., Hafey, M., Murphy, M.E. & George, D.L. : Mitochondrial p53 activates BAK and causes disruption of a BAK/MCL-1 complex. Nature Cell Biol. 6: 443-450, 2004.
Notes: Highlighted in a "News and Views" report: Perfettini, J-L, Kroemer, R.T. and Kroemer, G., Nature Cell Biol., 6:386-388, 2004 (PMID: 15122264).

Murphy, M.E., Leu, J.I-Ju and George, D. L. : p53 Moves to Mitochondria: A turn on the path to apoptosis. Cell Cycle 3: 836-839, 2004.

Dumont, P., Leu, J., Della Pietra III, A.C., George, D.L. and Murphy, M. : The codon 72 polymorphic variants of p53 demonstrate significant differences in apoptotic potential. Nature Genet. 2003.
Notes: Highlighted in two "Preview" reports: Manfredi, J.J., Mol. Cell, 11:552-554, 2003 (PMID: 12667439); Baptise, N. and Prives, C., Cell, 116: 487-489, 2004 (PMID:14980216).

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Lab

Rotation Projects

Rotation projects are determined on an individual basis and relate, in part, to the interests of the student and extent of previous laboratory experience.