The overall objective of this project is to elucidate the role of death domain-associated protein (Daxx) in regulating the tumor suppressor p53. p53 induces apoptosis, cell cycle, or senescence in response to a variety of stresses such as DNA damage and the activation of oncogenes. In unstressed cells, the potent anti-proliferative effects of p53 are restrained by Mdm2, a ubiquitin ligase (E3) that promotes rapid p53 ubiquitination and degradation. Stress signals activate p53 through the elevation of p53 levels, commonly via the disruption of the p53-Mdm2 interaction. In the case of DNA damage, this is due to phosphorylation of both p53 and Mdm2 and also due to Mdm2 self-ubiquitination. It is unclear how the cis- and trans-E3 activities of Mdm2, which have opposing effects on cell fate, are differentially regulated. The importance of p53 in tumor suppression is emphasized by the association of p53 mutations with nearly half of all human tumors. In the tumors that retain the wild type p53, p53 activity is often compromised through alterations in its regulatory proteins or effectors. However, for many tumors, the precise defects in the p53 pathway are not known. We recently found that Daxx plays a crucial role in the differential regulation of Mdm2's E3 activity. Daxx strongly promotes the stabilization of Mdm2 in unstressed cells by connecting Mdm2 to a de- ubiquitinase, Hausp. In addition, Daxx directly enhances the intrinsic E3 activity of Mdm2 towards p53. Upon DNA damage, Daxx dissociates from Mdm2, which precedes Mdm2 self-degradation and p53 activation. Furthermore, we found that Daxx is overexpressed in a large number of tumors. We hypothesize that Daxx is a crucial and multi-functional p53 inhibitor whose overexpression disables p53 in tumor cells. We will investigate the role of Daxx in modulating the E3 activity of Mdm2 (aim 1), elucidate the dynamic regulation of Daxx interactions and their contribution to p53 activation (aim 2), and determine the role of Daxx overexpression in tumorigenesis (aim 3). These studies will further define p53 regulation and its dysfunction in tumor cells. They may also reveal Daxx as a valuable diagnostic and therapeutic target in treating cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088868-09
Application #
7848254
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2001-05-03
Project End
2012-05-31
Budget Start
2010-06-03
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$253,024
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chen, Liang; Brewer, Michael D; Guo, Lili et al. (2017) Enhanced Degradation of Misfolded Proteins Promotes Tumorigenesis. Cell Rep 18:3143-3154
Guo, Lili; Prall, Wil; Yang, Xiaolu (2016) Assays for the Degradation of Misfolded Proteins in Cells. J Vis Exp :
Guo, Lili; Giasson, Benoit I; Glavis-Bloom, Alex et al. (2014) A cellular system that degrades misfolded proteins and protects against neurodegeneration. Mol Cell 55:15-30
Jiang, Peng; Du, Wenjing; Yang, Xiaolu (2013) A critical role of glucose-6-phosphate dehydrogenase in TAp73-mediated cell proliferation. Cell Cycle 12:3720-6
Jiang, Peng; Du, Wenjing; Mancuso, Anthony et al. (2013) Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493:689-93
Du, Wenjing; Jiang, Peng; Mancuso, Anthony et al. (2013) TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol 15:991-1000
Tang, Jun; Agrawal, Trisha; Cheng, Qian et al. (2013) Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation. PLoS One 8:e55813
Stevens, Kristen N; Kelemen, Linda E; Wang, Xianshu et al. (2012) Common variation in Nemo-like kinase is associated with risk of ovarian cancer. Cancer Epidemiol Biomarkers Prev 21:523-8
Kelemen, Linda E; Wang, Qinggang; Dinu, Irina et al. (2012) Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma. Front Genet 3:33
Jiang, Peng; Du, Wenjing; Wang, Xingwu et al. (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310-6

Showing the most recent 10 out of 36 publications