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.

Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library

“…These findings suggest that 9J10 may activate transcription factors other than FOXO3a that are engaged by the 14-3-3 family of signal regulators. Indeed, multiple transcription factors whose expression or activity can be altered in cancer cells are known to bind the 14-3-3 proteins ( Falcicchio et al., 2020 ; Mackintosh, 2004 ; Moon et al., 2017 ).…”

MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models

“…In various cancers, MDM2 overexpression is a prominent mechanism to impair P53 function. Studies of AML suggest that the TP53 mutation rate remains as low as 10% 17 – 20 , while MDM2 is frequently overexpressed 21 – 23 , rendering the P53-MDM2 axis an attractive pharmacologic target for small-molecule inhibitors.…”

Discovering protein–protein interaction stabilisers by native mass spectrometry

“…As a result, 14-3-3 modulates the subcellular localisation, protein folding, enzymatic activity or biomolecular interactions of the partner protein. 20 We chose to focus on three important 14-3-3 PPIs between 14-3-3s and LRRK2, 21 ERa 22 and p53 23,24 which are implicated with Parkinson's disease and cancer, and which are known to be differentially stabilised by fusicoccin A (FC-A). Estrogen receptor ERa has a characteristic 'mode 3' Cterminal 14-3-3 binding motif that binds to 14-3-3s, preventing ERa dimerization and thus inhibits its transcriptional activity which is a driver for breast cancer progression.…”