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.
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.
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|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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