Mutation of p53 is the most frequent genetic alteration in human cancer. The majority of tumor- derived p53 mutations is missense mutation and clustered within the central DNA-binding domain. Mutant p53 is defective in sequence-specific DNA binding and growth suppression, which defines the classical loss of function mutation. In addition, mutant p53 with an intact domain for tetramerization is dominant negative since the mutant can form a heterotetramer with wild-type p53. Moreover, mutant p53 acquires additional activity, called gain of function. Mutant p53 gain of function is recapitulated in knockn mice that carry one null allele and one mutant allele (R172H or R270H) of the p53 gene. These knockin mice develop aggressive tumors compared to p53-null mice. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for survival and resistance to DNA damage. Thus, the oncogenic properties of mutant p53 provide a rationale to target mutant p53 for cancer therapy, including the ones reactivating a mutant into wild-type-like. However, the large number of p53 mutations (>2,314 types of mutations;://www-p53.iarc.fr) poses a major challenge to develop versatile p53-reactivating drugs, especially considering that a modification and/or physical interaction is needed to convert a mutant into wild-type-like. Furthermore, a number of p53 mutants, when stabilized, associate with and inhibit other p53 family tumor suppressors (i.e., p63 and p73), which would then enhance gain of function for these p53 mutants. Thus, we hypothesize that targeting mutant p53 expression is a viable therapeutic strategy for tumors addicted to mutant p53. To further address this, three specific aims are proposed: (1) to determine how mutant p53 expression is transcriptionally regulated by histone deacetylases (HDACs), particularly HDAC8 and the biological significance of HDAC8 regulation of mutant p53 expression;(2) to determine the biological significance of RNPC1 regulation of mutant p53 expression and whether RNPC1 expression is suppressed in human tumors carrying a mutant p53;and (3) to determine how mutant p53 protein stability is regulated by arsenic and whether arsenic can suppress mutant p53-induced cell transformation and tumor progression.

Public Health Relevance

Mutant p53 is a leading oncogene in human cancer since more than 50% of tumors carry mutant p53. Recently, we and others showed that tumor cells carrying a mutant p53 are addicted to the mutant for survival and resistance to DNA damage. These properties provide a rationale to target mutant p53 for cancer therapy. To address this, three specific aims are proposed to explore how mutant p53 expression is regulated at the level of transcription, translation, and protein stability. Thus, the proposed study is highly relevant t public health. First, the proposed study in aim 1 will reveal the role of mutant p53 in HDAC inhibitor-mediated growth suppression, which might be further explored for cancer therapy. Second, the RNPC1-mutant p53 pathway might be targeted for cancer therapy. Third, arsenic is a drug to treat acute promyelocytic leukemia at least in part due to degradation of PML-RAR?, which prompts us to examine the potential effect of arsenic on mutant p53. Thus, the proposed study in aim 3 will provide an insight into expanding the use of arsenic as a drug (or an adjuvant) for tumors addicted to mutant p53.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA121137-07A1
Application #
8391661
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2006-04-01
Project End
2017-05-31
Budget Start
2012-08-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$283,822
Indirect Cost
$99,522
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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
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
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
Cao, Ruibing; Zhang, Jin; Zhang, Min et al. (2015) PPM1D regulates p21 expression via dephoshporylation at serine 123. Cell Cycle 14:641-7
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
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
Yan, Wensheng; Jung, Yong-Sam; Zhang, Yanhong et al. (2014) Arsenic trioxide reactivates proteasome-dependent degradation of mutant p53 protein in cancer cells in part via enhanced expression of Pirh2 E3 ligase. PLoS One 9:e103497
Jiang, Yuqian; Zhang, Min; Qian, Yingjuan et al. (2014) Rbm24, an RNA-binding protein and a target of p53, regulates p21 expression via mRNA stability. J Biol Chem 289:3164-75
Zhang, Jin; Xu, Enshun; Ren, Cong et al. (2014) Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors. Proc Natl Acad Sci U S A 111:18637-42
Zhang, Jin; Xu, Enshun; Chen, Xinbin (2013) Regulation of Mdm2 mRNA stability by RNA-binding protein RNPC1. Oncotarget 4:1121-2

Showing the most recent 10 out of 30 publications