THE P53/SOX2 AXIS IN MODULATING THE CELL FATE IN NEURONS: A PARADIGM OF NEURODEGENERATION AND BRAIN TUMORS

Abstract

Tumor suppressor p53 is a transcription factor associated with apoptosis or programmed cell death as it activates several caspases and downstream apoptotic signaling cascades, leading to cell death. Apoptosis is crucial for maintaining different cellular and biological processes within the organism, like genome stability and integrity, and cell cycle regulation. Apoptosis plays a major role in the progression of neurodegenerative diseases (NDDs) like Parkinson’s disease (PD), where substantial loss of neuronal cells, which secrete Dopamine, takes place, mediated by upregulated expression of p53 protein. p53 also interacts with the gene promoter of Bax, a Bcl2 family pro-apoptotic protein, directly upregulating its expression in the cell. Upregulation of Bax has many significant consequences within a cell, such as mitochondrial membrane disruption and excessive release of cytochrome-c from the mitochondria, which triggers a caspase-dependent apoptotic pathway. Interestingly, the Bax/Bak axis can also function in a p53-independent manner in response to TNF-α to activate apoptosis. Thus, exploring the relationship between p53 and Bax is crucial for marking the progression of apoptosis in neurodegenerative diseases like Parkinson’s disease. In this study, we have focused on the effect of such mutations on the structural configuration of p53 and its relationship with MDM2 and p53-Bax-mediated mitochondrial dysfunction which contribute to apoptosis and neuron death. We have targeted the missense single-nucleotide polymorphic (msSNPs) variants of p53, obtained from NCBI and UniProtKB, which have not been extensively studied. Structural stability and evolutionary studies, using tools like I-Mutant and ConSurf, identified eight SNPs as the most conserved, which were further utilized in this study. In MutPred2, PANTHER. and SNP&GO, all eight msSNPs were found to be deleterious according to their structural implications on the protein, suggesting that apoptosis in cells with these p53 mutations might be altered. To confirm these hypotheses, we conducted docking studies of these p53 variants with the MDM2 (inhibitor of p53) and Bax gene promoter, which, interestingly, showed low binding affinities with the former and high binding affinities with the latter as compared to the WT-p53, suggesting an increase in mitochondrial stress and dysfunction, which activates a series of apoptotic events leading to death of the cell. On the other hand, SOX2 is reported to be involved in several signaling pathways such as EGFR/MAPK/P13K-mTOR-AKT signaling pathway, SHH pathway, HIPPO signaling pathway, Wnt/β-catenin signaling pathway which plays a crucial role in the maintenance of cancer stem cell-like properties, tumor aggression, poor prognosis, drug resistance, invasion and migration in several brain tumors including Glioblastoma. Furthermore, recent studies suggest that p53 directly upregulate the gene expression of SOX2 in certain conditions. Additionally, there function is involved and overlap in the AKT signaling which suggest that these interplay between these proteins is crucial and can play an important role in determining the fate of the neuronal cells in diseased conditions, whether they take the path of programmed cell death and contribute to neurodegeneration or proliferation indefinitely to form brain tumors. Further in vivo and in vitro studies are required to validate these hypotheses and provide new insights into drug targeting that disrupts this p53/SOX2 axis and potential therapeutic strategies for treating neurodegenerative diseases and brain tumors.