The p53 tumor suppressor gene product is a key mediator of cell cycle arrest and apoptosis in response to genotoxic stress. These responses are essential to prevent the emergence of transformation-prone cells with unstable genomes. The biological role of p53 as a DNA damage checkpoint is directly attributable to its biochemical function as a sequence-specific transcriptional activator. Indeed, nearly all cancer-associated p53 mutations abrogate this function. The transactivation function of p53 requires accessory protein complexes, the coactivators, such as the p300/CBP family. We have identified hADA complex, the homologue of the yeast ADA complex, as a novel coactivator of p53. We hypothesize that histone acetyl transferase (HAT)-containing hADA complex, either by itself or in concert with p300/CBP, regulates either the extent or the nature of p53-mediated DNA damage response by acetylating p53 and chromatin-associated histones in p53 target promoters.To address these hypotheses, we will first characterize the components of human ADA complex in cells under study, determine if ADA3 is the component that recruits ADA complex to p53, as our preliminary results suggest, and use mutagenesis to map the ADA3 and p53 domains, that mediate their interaction. We will use overexpression and dominant-negative approaches to investigate if ADA complex functions as a coactivator for p53, and determine if coactivator function relates to histone acetylation on p53 target gene promoters and/or p53 acetylation. Finally, we will quantify p53-mediated cell cycle arrest and apoptotic responses to DNA damage to assess the role of ADA complex versus p300/CBP in regulating p53-mediated DNA damage response, using overexpression as well as dominant-negative strategies. A successful outcome of the proposed studies should identify a novel mechanism for regulating p53-mediated DNA damage response, and provide potential targets for future development of diagnostic agents and rational therapeutics for human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA096844-01
Application #
6521549
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Blair, Donald G
Project Start
2002-08-15
Project End
2003-06-30
Budget Start
2002-08-15
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$288,063
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Luan, Haitao; Mohapatra, Bhopal; Bielecki, Timothy A et al. (2018) Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program. Cancer Res 78:2524-2535
Iseka, Fany M; Goetz, Benjamin T; Mushtaq, Insha et al. (2018) Role of the EHD Family of Endocytic Recycling Regulators for TCR Recycling and T Cell Function. J Immunol 200:483-499
Olou, Appolinaire A; Sarkar, Aniruddha; Bele, Aditya et al. (2017) Mammalian ECD Protein Is a Novel Negative Regulator of the PERK Arm of the Unfolded Protein Response. Mol Cell Biol 37:
Nadeau, Scott A; An, Wei; Mohapatra, Bhopal C et al. (2017) Structural Determinants of the Gain-of-Function Phenotype of Human Leukemia-associated Mutant CBL Oncogene. J Biol Chem 292:3666-3682
Mohapatra, Bhopal; Zutshi, Neha; An, Wei et al. (2017) An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Development 144:1072-1086
Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal et al. (2016) Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition. Oncotarget 7:10522-35
Bhagirath, Divya; Zhao, Xiangshan; Mirza, Sameer et al. (2016) Mutant PIK3CA Induces EMT in a Cell Type Specific Manner. PLoS One 11:e0167064
Cypher, Luke R; Bielecki, Timothy Alan; Adepegba, Oluwadamilola et al. (2016) CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface. Cell Signal 28:1325-35
Bhattacharyya, Sohinee; Rainey, Mark A; Arya, Priyanka et al. (2016) Endocytic recycling protein EHD1 regulates primary cilia morphogenesis and SHH signaling during neural tube development. Sci Rep 6:20727
An, Wei; Mohapatra, Bhopal C; Zutshi, Neha et al. (2016) VAV1-Cre mediated hematopoietic deletion of CBL and CBL-B leads to JMML-like aggressive early-neonatal myeloproliferative disease. Oncotarget 7:59006-59016

Showing the most recent 10 out of 70 publications