Abstract
The TP53 tumor suppressor gene is frequently inactivated in human tumors by missense mutations in the DNA binding domain. TP53 mutations lead to protein unfolding, decreased thermostability and loss of DNA binding and transcription factor function. Pharmacological targeting of mutant p53 to restore its tumor suppressor function is a promising strategy for cancer therapy. The mutant p53 reactivating compound APR-246 (PRIMA-1Met) has been successfully tested in a phase I/IIa clinical trial. APR-246 is converted to the reactive electrophile methylene quinuclidinone (MQ), which binds covalently to p53 core domain. We identified cysteine 277 as a prime binding target for MQ in p53. Cys277 is also essential for MQ-mediated thermostabilization of wild-type, R175H and R273H mutant p53, while both Cys124 and Cys277 are required for APR-246-mediated functional restoration of R175H mutant p53 in living tumor cells. These findings may open opportunities for rational design of novel mutant p53-targeting compounds.
Highlights
Tumor suppressor p53 is a transcription factor that responds to cellular stress, e.g., DNA damage and oncogene activation. p53 triggers cell cycle arrest, senescence and apoptosis[1,2]
APR-246 has been tested in a phase I/IIa clinical trial in patients with hematological malignancies or prostate cancer[24]
32% of the wt and R273H p53 core domain proteins were modified by one methylene quinuclidinone (MQ) molecule when incubated with lower concentrations of MQ (Fig. 1b), and that all p53 protein molecules had two MQ adducts upon incubation with μM MQ (Fig. 1d)
Summary
Tumor suppressor p53 is a transcription factor that responds to cellular stress, e.g., DNA damage and oncogene activation. p53 triggers cell cycle arrest, senescence and apoptosis[1,2]. The TP53 gene is inactivated in a large fraction of human tumors[7,8]. The majority of TP53 mutations are missense mutations resulting in substitution of amino acid residues that make direct contact with DNA, such as R248W and R273H, or residues that are important for the structural integrity of the core domain, e.g. R175H and R249S. This leads to loss of specific DNA binding[9]. The high frequency of TP53 mutations in human tumors has stimulated efforts to develop therapeutic strategies for targeting mutant p53 in cancer.
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