p73, a member of the p53 family of tumor suppressors, is expressed from two promoters: the upstream P1 promoter that produces TAp73 and the downstream P2 promoter that produces ?Np73. Additionally, p73 is expressed as six isoforms (????????????????) through alternative splicing between exon 11-13. As a transcription factor, we and others showed that TAp73 contains an activation domain similar to the first activation domain (AD1) in p53. We also identified a unique activation domain in ?Np73. Thus, TAp73 and ?Np73 are capable of inducing a distinct set of target genes. Consistent with its transcriptional activity, mice deficient in TAp73 are prone to spontaneous tumors and accelerated aging whereas mice deficient in ?Np73 are prone to neurological defects. However, compared to TA and ?N isoforms, very little is known about p73 C-terminal isoforms and their activities in vivo. Now, by using CRISPR-cas9 method to delete one or more exons in the p73 gene in cell lines and in mice, we are able to systematically study the role of p73 C-terminal isoforms in vitro and in vivo. Our preliminary data showed that various p73 C-terminal isoforms have distinct activities. Thus, we hypothesize that each p73 C-terminal isoform has a unique function in tumor suppression and longevity. To test this, we will determine: (1) C-terminal isoform-specific activities in cell growth and differentiation; (2) C-terminal isoform-specific activities in tumor suppression and longevity; (3) C-terminal isoform-specific effects on tumorigenesis in p53-deficient or mutant p53R270H knockin mice.

Public Health Relevance

The proposed study is highly significant and relevant to human health: (1) this study would provide better understanding of p73 biology and lay a foundation for exploring p73 as a target for cancer management and/or longevity; (2) this study would reveal whether mutant p53 antagonizes p73 in vivo and whether p73 might be harnessed to target tumors harboring a mutant p53.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081237-22
Application #
10083713
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
1999-05-01
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
22
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zhang, Jin; Chen, Xinbin (2018) p53 tumor suppressor and iron homeostasis. FEBS J :
Lucchesi, Chris; Zhang, Jin; Chen, Xinbin (2016) Modulation of the p53 family network by RNA-binding proteins. Transl Cancer Res 5:676-684
Yan, Wensheng; Scoumanne, Ariane; Jung, Yong-Sam et al. (2016) Mice deficient in poly(C)-binding protein 4 are susceptible to spontaneous tumors through increased expression of ZFP871 that targets p53 for degradation. Genes Dev 30:522-34
Zhang, Min; Zhang, Jin; Yan, Wensheng et al. (2016) p73 expression is regulated by ribosomal protein RPL26 through mRNA translation and protein stability. Oncotarget 7:78255-78268
Zhang, Jin; Lucchesi, Christopher; Chen, Xinbin (2016) A new function for p53 tetramerization domain in cell fate control. Cell Cycle 15:2854-2855
Ren, Cong; Zhang, Jin; Yan, Wensheng et al. (2016) RNA-binding Protein PCBP2 Regulates p73 Expression and p73-dependent Antioxidant Defense. J Biol Chem 291:9629-37
Wang, Junjian; Wang, Haibin; Wang, Ling-Yu et al. (2016) Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. Cell Death Differ 23:1886-1896
Zhang, M; Xu, E; Zhang, J et al. (2015) PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38. Oncogene 34:5900-11
Cho, Seong-Jun; Teng, I-Fang; Zhang, Min et al. (2015) Hypoxia-inducible factor 1 alpha is regulated by RBM38, a RNA-binding protein and a p53 family target, via mRNA translation. Oncotarget 6:305-16
Zhang, Yanhong; Young, Ashley; Zhang, Jin et al. (2015) P73 tumor suppressor and its targets, p21 and PUMA, are required for madin-darby canine kidney cell morphogenesis by maintaining an appropriate level of epithelial to mesenchymal transition. Oncotarget 6:13994-4004

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