Abstract
Simple Summaryp53, a critical tumor suppressor, is commonly mutated in neoplasia, including colorectal cancer. To devise anti-cancer strategies targeting p53, it is crucial to understand the myriad cell-specific regulatory mechanisms in the p53 signaling pathway, and how these same regulatory mechanisms may be evaded by p53 mutants. This review focuses on colorectal cancer and considers the regulatory mechanisms underlying the actions of wild type p53 protein, emphasizing discoveries made in the last decade. We focus on the role of mouse double minute 2 homolog (MDM2), which modulates p53 protein levels by targeting p53 for protein degradation; other MDM2-independent mechanisms are also discussed. These regulatory mechanisms are further examined in the context of p53 missense mutants, which can evade canonical regulation. Lastly, we consider potential strategies for therapeutic targeting of p53 mutant-bearing cancers in preclinical testing or early-phase clinical trials.The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.
Highlights
In sporadic colorectal cancer (CRC), the most common form, loss of p53 function is a critical step in the adenoma-to-adenocarcinoma transition; p53 mutations are detected in 55–60%
mouse double minute 2 homolog (MDM2) can bind and ubiquitinate mutp53, with decreased efficiency compared to wild-type p53 [90,91]
Novel p53 regulators contribute to the increasingly complex p53 regulatory network, but some are context-dependent and not all contribute to CRC progression
Summary
In sporadic CRC, the most common form, loss of p53 function is a critical step in the adenoma-to-adenocarcinoma transition; p53 mutations are detected in 55–60%. Some p53 mutations exhibit gain-of-function properties that ‘supercharge’ tumor growth and metastasis. Adding to this complexity is the observation that p53 network regulation varies between cell types. To devise effective therapeutic strategies to target p53, it is crucial to gain a comprehensive understanding of p53 dysregulation. We examined post-translational regulatory mechanisms underlying p53 homeostasis, focusing on discoveries made in the last decade and shedding light on how p53 mutants escape regulatory controls in the context of CRC. We conclude by discussing gaps in knowledge and how what we know can be applied to develop therapeutic strategies directed against p53 mutants.
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