Abstract
The wild-type protein p53 plays a key role in preventing the formation of neoplasms by controlling cell growth. However, in more than a half of all cancers, the TP53 gene has missense mutations that appear during tumorigenesis. In most cases, the mutated gene encodes a full-length protein with the substitution of a single amino acid, resulting in structural and functional changes and acquiring an oncogenic role. This dual role of the wild-type protein and the mutated isoforms is also evident in the regulation of the redox state of the cell, with antioxidant and prooxidant functions, respectively. In this review, we introduce a new concept of the p53 protein by discussing its sensitivity to the cellular redox state. In particular, we focus on the discussion of structural and functional changes following post-translational modifications of redox-sensitive cysteine residues, which are also responsible for interacting with zinc ions for proper structural folding. We will also discuss therapeutic opportunities using small molecules targeting cysteines capable of modifying the structure and function of the p53 mutant isoforms in view of possible anticancer therapies for patients possessing the mutation in the TP53 gene.
Highlights
Oxidative damage to proteins has a critical role in promoting several disorders such as degenerative diseases and cancer [1,2]
We summarize the redox-sensitive cysteine residues of wild-type and mutant p53, describing cysteine oxidative post-translational modifications to highlight their importance as target therapy for promoting p53 correct folding and activity and regulating mutant p53 oxidative responses
The oncosuppressor p53 protein acts as a transcription factor and contains different functional domains: (i) N-terminal transactivation domain (TAD) which interacts with the transcriptional machinery; (ii) proline rich-region (PRD), which is required for p53 stabilization; (iii) DNA binding domain (DBD), in which the responsive element binds proteins such as MDM2 and 53BP1 that, respectively, positively or negatively affect p53 activity; (iv) oligomerization domain (TET) which is essential for tetramer formation and represents the active form of p53 and (v) C-terminal regulatory domain (REG), containing post-translationally modified residues involved in modulation of protein stability [12]
Summary
Oxidative damage to proteins has a critical role in promoting several disorders such as degenerative diseases and cancer [1,2]. Cysteine residues of proteins have both structural and regulatory roles and are susceptible to oxidation [4]. This reactivity leads the cysteine residues to act as redox-sensitive molecular sensors or switches with catalytic activity and metal binding capacity that are oxidative status-dependent [4,5]. In contrast with the wild-type protein, mutant p53 isoforms counteract antioxidant activity and enhance intracellular ROS, influencing the cellular redox balance and promoting cancer survival [11]. We summarize the redox-sensitive cysteine residues of wild-type and mutant p53, describing cysteine oxidative post-translational modifications to highlight their importance as target therapy for promoting p53 correct folding and activity and regulating mutant p53 oxidative responses
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