PIN1’s Crucial Role for P53 Expression and Activation
The tumor suppressor p53 and the proto-oncogene Bcl-2 were two of the earliest identified cancer-related genes [195]. p53 is a global transcription factor that maintains the integrity of the cell under stressful conditions through its activation of expression of many proteins involving cell cycle arrest and DNA repair as part of the DNA stress response. p53 in the cytoplasm also plays an important role in safeguarding the mitochondria from DNA damage [196]. PIN1 deficiency results in defective p53 transactivation [197,198], and p53 transactivation is reduced in association with autism [199]. Knocking down of p53 in mice significantly promotes repetitive behavior and reduces sociability, clear signs of autism [177,197].
In addition to its role in DNA protection from toxic exposures, p53 is important in hippocampal neurons for learning and memory. Lee et al. wrote in their abstract: “Altogether, our study suggests p53 as an activity-dependent transcription factor that mediates the surface expression of AMPAR, permits hippocampal synaptic plasticity, represses autism-like behavior, and promotes hippocampus-dependent learning and memory” [177]. A study published in 2023 demonstrated that glyphosate activates microglia via toll-like 4 receptor (TLR4) and triggers cellular stress, resulting in impaired hippocampal plasticity and learning [200].
Under quiescent conditions, p53 remains bound to MDM2, an E3 ubiquitin ligase that promotes its constant proteasomal degradation, maintaining the protein at low levels. Upon stress activation, p53’s localization to the nucleus depends upon binding to PIN1. Genotoxic exposures induce the phosphorylation and activation of p53 on its Ser/Thr-Pro motifs, and this allows PIN1 to isomerize critical proline residues in p53. PIN1 in turn stimulates the DNA-binding activity and transactivation functions of p53. PIN1-deficient cells are defective in p53 activation, and this results in impaired checkpoint control in response to DNA damage [198].
Lack of PIN1 also leads to increased destabilization of p53 by its inhibitor, MDM2. Thr81-Pro82 is a crucial site for PIN1 to promote checkpoint kinase 2- (Chk2)-dependent phosphorylation of p53 on Ser20. This serine phosphorylation modification stimulates the dissociation of p53 from MDM2, protecting it from ubiquitination and degradation [198,201].
p53 still induces cell death when it is impaired in its ability to localize to the nucleus. When PIN1 levels are low under stressful conditions, p53 accumulates in the cytoplasm, where it can induce death by apoptosis or necrosis [202,203]. p53 interacts in the cytoplasm with Bcl-2, the founding member of the Bcl-2 family of proteins that regulate cell death, to suppress its anti-apoptotic activity, thus sensitizing the cell to apoptosis via permeabilization of mitochondria [195]. This extranuclear influence of p53 has been coined as transcription-independent p53-induced apoptosis (TIPA) [204]. p53 can also inhibit cystine uptake, leading to ferroptosis due to glutathione depletion [205]. Cytoplasmic, but not nuclear, p53 suppresses macroautophagy, through activation of the mTOR pathway [206,207]. We will return to this topic in a later section since it pertains to autism.
Palmitate is the most common saturated fatty acid in food, but it can lead to lipotoxicity and apoptosis in exposed cells. p53 provides some protection against palmitate-induced apoptosis through its activation of gene expression of DNA-protective proteins. However, this depends upon its ability to translocate to the nucleus, which in turn depends upon PIN1. Experimentally, cell lines from p53-/- mice were significantly more sensitive to apoptosis through excessive ROS in response to excess palmitate exposure [208].