Source: UNIVERSITY OF CALIFORNIA, DAVIS submitted to NRP
MECHANISMS OF P73-DEPENDENT TUMOR SUPPRESSION
Sponsoring Institution
Cooperating Schools of Veterinary Medicine
Project Status
COMPLETE
Funding Source
STATE
Reporting Frequency
Annual
Accession No.
0213334
Grant No.
(N/A)
Cumulative Award Amt.
(N/A)
Proposal No.
(N/A)
Multistate No.
(N/A)
Project Start Date
Feb 20, 2007
Project End Date
Feb 28, 2014
Grant Year
(N/A)
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
The mechanism by which mutant p53 acquires a gain of function remains unclear. It is important to characterize the molecular oncogenic properties of mutant p53 and to identify mutant p53 target genes. A successful completion of this project will help scientists to identify and target one or more oncogenic properties of mutant p53 for cancer management.
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
3113840103010%
3113840104010%
3113840108010%
3113840116070%
Knowledge Area
311 - Animal Diseases;

Subject Of Investigation
3840 - Laboratory animals;

Field Of Science
1040 - Molecular biology; 1030 - Cellular biology; 1160 - Pathology; 1080 - Genetics;
Goals / Objectives
p73, a member of the p53 tumor suppressor family, is involved in the DNA damage response and serves as a mediator of p53 tumor suppression. Like p53, p73 is a sequence-specific DNA-binding transcription factor and an important regulator in the control of the cell cycle and apoptosis, p73 is expressed as three major variants, TA, DN, and DTA. The TA variant is transcribed from the upstream promoter and produces at least seven alternatively spliced TA isoforms (p73a-h), which differ in their carboxyl termini. The DN variant is transcribed from an alternate promoter in intron 3 and similarly produces at least another seven alternatively spliced DN isoforms (DNp73a-h). Since the N-terminal activation domain is absent in the DN variant, it is hypothesized that the DN variant is transcriptionally inactive and potentially dominant negative over the TA variant and possibly over p53. Interestingly, we have found and, later several other groups have confirmed, that the DN variant of the p53 family member p63, which also lacks the N-terminal activation domain, is transcriptionally active and capable of inducing specific target genes. We hypothesize that DNp73 is transcriptionally active and exerts its function by regulating specific target genes. Since p73 is 63% identical in amino acid to p53 in the DNA-binding domain, it can regulate some p53 target genes, presumably via the p53 responsive element. However, we found that the functional domains in p73 are different from that in p53. We also found that while p73 regulates IGFBP3 and GADD45, it does not regulates a luciferase reporter under the control of the p53 responsive element found in both genes. Thus, we hypothesize that p73 regulates some target genes through its unique responsive element.
Project Methods
This project will be addressed in three aims: (1) to analyze the activity of the DN variant of p73, (2) to determine the mechanism by which various p73 isoforms differentially regulate IGFBP3 and GADD45, and (3) to determine the role of IGFBP3 and GADD45 in mediating p73 function.

Progress 10/01/13 to 02/28/14

Outputs
Target Audience:A progress report was submitted to the funding agency. Changes/Problems:A progress report was submitted to the funding agency. What opportunities for training and professional development has the project provided?A progress report was submitted to the funding agency. How have the results been disseminated to communities of interest?A progress report was submitted to the funding agency. What do you plan to do during the next reporting period to accomplish the goals?A progress report was submitted to the funding agency.

Impacts
What was accomplished under these goals? A progress report was submitted to the funding agency.

Publications


    Progress 02/20/07 to 02/28/14

    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? Final Report was submitted to the funding agency

    Publications


      Progress 10/01/12 to 09/30/13

      Outputs
      Target Audience:A progress report was submitted to the funding agency. Changes/Problems:A progress report was submitted to the funding agency. What opportunities for training and professional development has the project provided?A progress report was submitted to the funding agency. How have the results been disseminated to communities of interest?A progress report was submitted to the funding agency. What do you plan to do during the next reporting period to accomplish the goals?A progress report was submitted to the funding agency.

      Impacts
      What was accomplished under these goals? A progress report was submitted to the funding agency.

      Publications


        Progress 10/01/11 to 09/30/12

        Outputs
        Target Audience:A progress report was submitted to the funding agency. Changes/Problems:A progress report was submitted to the funding agency. What opportunities for training and professional development has the project provided?A progress report was submitted to the funding agency. How have the results been disseminated to communities of interest?A progress report was submitted to the funding agency. What do you plan to do during the next reporting period to accomplish the goals?A progress report was submitted to the funding agency.

        Impacts
        What was accomplished under these goals? A progress report was submitted to the funding agency.

        Publications


          Progress 10/01/10 to 09/30/11

          Outputs
          Target Audience:A progress report was submitted to the funding agency. Changes/Problems:A progress report was submitted to the funding agency. What opportunities for training and professional development has the project provided?A progress report was submitted to the funding agency. How have the results been disseminated to communities of interest?A progress report was submitted to the funding agency. What do you plan to do during the next reporting period to accomplish the goals?A progress report was submitted to the funding agency.

          Impacts
          What was accomplished under these goals? A progress report was submitted to the funding agency.

          Publications


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

            Outputs
            Target Audience:Progress reports for this project were submitted to the Sponsoring Agency Changes/Problems:Progress reports for this project were submitted to the Sponsoring Agency What opportunities for training and professional development has the project provided?Progress reports for this project were submitted to the Sponsoring Agency How have the results been disseminated to communities of interest?Progress reports for this project were submitted to the Sponsoring Agency What do you plan to do during the next reporting period to accomplish the goals?Progress reports for this project were submitted to the Sponsoring Agency

            Impacts
            What was accomplished under these goals? Progress reports for this project were submitted to the Sponsoring Agency

            Publications


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

              Outputs
              OUTPUTS: Research accomplishments RNPC1 is induced by p73. NGF-mediated neuronal cell differentiation is regulated by Np73 Identification of Dec1 as a novel target of p73 Dec1 is a potential mediator of p73 in inducing cellular senescence PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

              Impacts
              Research accomplishments RNPC1 is induced by p73. NGF-mediated neuronal cell differentiation is regulated by Np73 Identification of Dec1 as a novel target of p73 Dec1 is a potential mediator of p73 in inducing cellular senescence

              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.