The p53 protein plays a critical role in tumor suppression, and represents a pivotal mediator of cellular responses to both intrinsic and extrinsic stress signals. As a nuclear transcription factor, p53 has the ability to activate, or repress, the expression a large number of genes. Accumulating evidence suggests that p53 also has a non-transcriptional function with a direct role at mitochondria in promoting apoptosis. The outcome of stress-mediated p53 activation generally is growth arrest or cell death (apoptosis). How this """"""""decision"""""""" is made remains an unresolved question in the field, and is described in general terms as being determined by """"""""cell context"""""""" or by the balance of prosurvival or proapoptotic factors. Thus, the goal of defining and characterizing key cellular determinants that control this important decision and mediate the diverse activities of p53 is of central importance in cancer biology. The focus of this research project centers on our very recent discovery of a functional link between a liver survival factor, insulin-like growth factor binding protein 1 (IGFBP1), and the p53 protein. While in many tissues, p53 activation leads to cell death, our data suggest that p53 in liver cells also has a cytoprotective role. Thus, a primary goal will be to investigate whether a p53/IGFBP1 feed-back circuit is part of a crucial pathway mediating the stress- response outcome of normal and neoplastic liver cells. These investigations center on important issues related to the ways p53 acts in response to stress, including: the contribution of mitochondrial p53 to apoptosis, the identification and characterization of critical modulators of p53 function, and the factors that determine whether stress-activated p53 will promote survival or apoptosis. In conjunction, they address the intracellular mechanism of action of the prosurvival/proregeneration protein, IGFBP1. The information obtained will provide an essential framework needed for development of greater insight into decisions that influence cell death signaling mechanisms in normal and neoplastic liver cells, an understanding that is needed for the rational design of effective therapeutic strategies in treating cancers and hepatic diseases that predispose to cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118761-04
Application #
7860452
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2007-08-07
Project End
2012-05-31
Budget Start
2010-06-03
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$299,250
Indirect Cost
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Leu, Julia I-Ju; Murphy, Maureen E; George, Donna L (2013) The p53 Codon 72 Polymorphism Modifies the Cellular Response to Inflammatory Challenge in the Liver. J Liver 2:
Balaburski, Gregor M; Leu, Julia I-Ju; Beeharry, Neil et al. (2013) A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res 11:219-29
Leu, J I-Ju; Pimkina, Julia; Pandey, Pooja et al. (2011) HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells. Mol Cancer Res 9:936-47
Leu, J I-Ju; Pimkina, Julia; Frank, Amanda et al. (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15-27
Leu, J I-Ju; George, Donna L (2007) 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 21:3095-109