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].