SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

Abstract

Stemness and reprogramming involve transcriptional master regulators that suppress cell differentiation while promoting self-renewal. A distinguished example thereof is SOX2, a high mobility group (HMG)-box transcription factor (TF), whose subcellular localization and turnover regulation in embryonic, induced-pluripotent, and cancer stem cells (ESCs, iPSCs, and CSCs, respectively) is mediated by the PI3K/AKT/SOX2 axis, a stem cell-specific branch of the PI3K/AKT signaling pathway. Further effector functions associated with PI3K/AKT induction include cell cycle progression, cellular (mass) growth, and the suppression of apoptosis. Apoptosis, however, is a central element of DNA damage response (DDR), where it provides a default mechanism for cell clearance when DNA integrity cannot be maintained. A key player in DDR is tumor suppressor p53, which accumulates upon DNA-damage and is counter-balanced by PI3K/AKT enforced turnover. Accordingly, stemness sustaining SOX2 expression and p53-dependent DDR mechanisms show molecular–functional overlap in PI3K/AKT signaling. This constellation proves challenging for stem cells whose genomic integrity is a functional imperative for normative ontogenesis. Unresolved mutations in stem and early progenitor cells may in fact provoke transformation and cancer development. Such mechanisms are also particularly relevant for iPSCs, where genetic changes imposed through somatic cell reprogramming may promote DNA damage. The current review aims to summarize the latest advances in the understanding of PI3K/AKT/SOX2-driven stemness and its intertwined relations to p53-signaling in DDR under conditions of pluripotency, reprogramming, and transformation.

Electromagnetic field exposure as a plausible approach to enhance the proliferation and differentiation of mesenchymal stem cells in clinically relevant scenarios

“…In their study, Fan et al (2015) proposed that the induced FGF-2 may inhibit cellular senescence and promote cellular proliferation via the phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT)-mouse double minute 2 (MDM2) signaling pathway. This notion is in agreement with recent studies that proposed the involvement of PI3K/AKT signaling as one of key players in the maintenance of self-renewal and stemness of MSCs (Fong et al, 2007;Schaefer et al, 2020). The in-depth explanation regarding EMF interaction with biological cells may open a new perspective, in particular in the application of EMF to MSCs, as depicted in Fig.…”

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

“…We also validated several of the top up- and downregulated genes mediated by TRIB2 overexpression in both untreated and BEZ235-treated cells ( Figure 1 D–G) by using RT-qPCR. The top genes were chosen from the list of differentially expressed genes ( Figure 1 C), from which we selected the 10 most upregulated and 10 most downregulated genes by TRIB2, as well as genes described to be involved in cancer proliferation and survival, namely Keratin 14 (KRT14), SRY-Box Transcription Factor 2 (SOX2), Formin-like protein 2 (FMNL2), BCL2-associated X, apoptosis regulator (BAX), TNF superfamily member 10 (TNFSF10), CEBPA, baculoviral IAP repeat-containing protein 7 (BIRC7), KiSS-1 metastasis suppressor (KISS1), Sestrin 2 (SESN2), MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) and BCL2 Binding Component 3 (PUMA) ( Figure 1 D–G) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. KRT14, SOX2 and FMNL2 were upregulated by TRIB2 and downregulated by BEZ235 treatment, while BAX, TNFSF10 and CEBPA were downregulated by TRIB2 ( Figure 1 D).…”

New Therapeutic Opportunities for the Treatment of Squamous Cell Carcinomas: A Focus on Novel Driver Kinases

“…TP63 is a direct transcriptional target of SOX2 and controls numerous genes involved in cellular differentiation and growth, including the aforementioned FGFR1 [ 9 , 42 ]. However, cellular reliance on p63 and SOX2 seems to diminish as the tumor grows, and increasing evidence suggests the loss of these proteins is correlated with tumor metastasis [ 43 , 44 ]. No FDA-approved small molecule inhibitors exist for either SOX2 or p63, so other targetable oncogenic proteins within the 3q amplicon need to be identified for the development of efficacious SCC therapies.…”