MOLECULAR ONCOGENIC PROPERTIES OF MUTANT P53

• Sponsoring Institution: Cooperating Schools of Veterinary Medicine
• Project Status: COMPLETE
• Funding Source: STATE
• Reporting Frequency: Annual
• Accession No.: 0213336
• Project Start Date: Jul 3, 2007
• Project End Date: Jan 31, 2012
• Program Code: [(N/A)]- (N/A)

Recipient Organization
UNIVERSITY OF CALIFORNIA, DAVIS
410 MRAK HALL
DAVIS,CA 95616-8671

Performing Department
Surgical And Radiological Sciences

Non Technical Summary
This project will address the molecular oncogenic properties of mutant p53. Mutations of the p53 gene are selected for in greater than 50% of all human cancers.

Animal Health Component

(N/A)

Research Effort Categories

Basic

(N/A)

Applied

(N/A)

Developmental

(N/A)

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
311	3840	1020	10%
311	3840	1030	10%
311	3840	1040	10%
311	3840	1160	70%

Knowledge Area
311 - Animal Diseases;

Subject Of Investigation
3840 - Laboratory animals;

Field Of Science
1040 - Molecular biology; 1030 - Cellular biology; 1160 - Pathology; 1020 - Physiology;

Keywords

p53 target genes

isoforms

cancer

tumor

che

Goals / Objectives
p53 tumor suppressor is a sequence-specific DNA-binding transcription factor. Wild-type p53 is activated in response to various stress signals, such as DNA damage, oncogene activation, and hypoxia. Following its activation, p53 suppresses damaged cells to proliferate by inducing downstream effects, such as cell cycle arrest and apoptosis. However, mutations in the p53 gene abrogate its transcriptional activity, leading to the uncontrolled proliferation characteristic of tumor cells. As a result, mutations of the p53 gene are selected for in greater than 50% of all human cancers. A vast majority of p53 mutations occur in its DNA-binding domain, rendering p53 defective in its DNA binding and transcriptional activities. This represents the classical loss of function mutation for a tumor suppressor. Interestingly, in addition to loss of function, many p53 mutants obtain additional activities, called gain of function. It is well known that in a cell carrying both wild-type and mutant p53, the mutant p53 acquires its gain of function by forming a heterotetramer with, and inhibiting the activity of, wild-type p53. However, the vast majority of tumor cells, which over-express a mutant p53, do not carry a wild-type p53. Thus, mutant p53 gain of function in these tumor cells must be due to its tumor-promoting activity independent of the inhibition of wild-type p53.

Project Methods
To further analyze how mutant p53 obtains its gain of function, the following specific aims are proposed: (1) to determine whether mutant p53 is required for maintaining the transformed phenotypes of tumor cells in evading apoptosis and enhanced potentials in proliferation and invasion; (2) to determine whether various classes of p53 mutants differ in their ability to maintain the transformed phenotypes of tumor cells; and (3) to determine whether mutant p53 still functions as a transcription factor that regulates genes involved in promoting survival or inhibiting anti-growth signals.

Progress 07/03/07 to 01/31/12

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? This proposal was submitted to a different sponsor and progress reports were submitted to the appropriate agency.

Publications

Progress 01/01/10 to 09/30/10

Outputs
Target Audience: Nothing Reported Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Nothing Reported How have the results been disseminated to communities of interest? Nothing Reported What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? This proposal was submitted to a different sponsor and progress reports were submitted to the appropriate agency.

Publications

Progress 01/01/09 to 12/31/09

Outputs
OUTPUTS: Research Accomplishment The gene encoding Gro1, a CXC chemokine, is identified as a mutant p53 target gene Knockdown of Gro1 abrogates mutant p53 gain-of-function Overexpression of Gro1 is capable of restoring cell proliferation in SW480 cells when mutant p53 is knocked down The activation domain and the proline-rich domain are required for mutant p53 gain-of-function whereas the C-terminal basic domain is disposable. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Research Accomplishment The gene encoding Gro1, a CXC chemokine, is identified as a mutant p53 target gene Knockdown of Gro1 abrogates mutant p53 gain-of-function Overexpression of Gro1 is capable of restoring cell proliferation in SW480 cells when mutant p53 is knocked down The activation domain and the proline-rich domain are required for mutant p53 gain-of-function whereas the C-terminal basic domain is disposable.

Publications

• Qian, Y. and X. Chen. 2008. ID1, inhibitor of differentiation/DNA binding, is an effector of the p53-dependent DNA damage response pathway. J. Biol. Chem. 283:22410-22416. PMCID: PMC2504896. Zhang, Y., L. Shu, and X. Chen. 2008. Syntaxin 6, a target of the p53 family, mediates the pro-survival function of the p53 family. J. Biol. Chem. 283: 30689-30698. PMCID: PMC2576542. Zhang, J., X. Chen, M. Kent, C. Rodriguez, and X. Chen. 2009. Establishment of a dog model for the p53 family pathway and identification of a novel isoform of p21 cyclin-dependent kinase inhibitor. Mol. Cancer Res. 7: 67-78. PMCID #85731. Zhang, J. and X. Chen. 2008. Posttranscriptional Regulation of p53 and Its Targets by RNA-Binding Proteins. Current Mol. Med.8: 845-849. PMCID #85733. Scoumanne, A. and X. Chen. 2008. Protein methylation: a novel regulator of the p53 tumor suppressor. Histology and Histopathology, 23:1143-1149. NIHMSID: 104491. Yan, W. and X. Chen. 2009. Gro-1 cytokine is a mediator of the gain-of-function p53 mutants. J. Biol. Chem. 284: 12178-12187. PMCID: PMC2673286. Qian, Y. and X. Chen. 2009. Tumor suppression by p53: making cells senescent. Histology and Histopathology, In press. Helton, E. S., J. Zhang, and X. Chen. 2008. The PXXP motif in p63 is involved in differential target gene regulation. Oncogene 27: 2843-2850. NIHMSID: 104358.