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Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer.

ABSTRACT: Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein-protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications.

SUBMITTER: Falcicchio M

PROVIDER: S-EPMC7669891 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer.

Falcicchio Marta M Ward Jake A JA Macip Salvador S Doveston Richard G RG

Cell death discovery 20201116 1

Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used ...[more]

PMID: 33298896

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Project description:Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

Dataset Information

Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer.

Publications

Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer.

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