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.
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.
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