Since its discovery in 1979, the p53 gene has been one of the focal points of oncology research. A search in the PubMed database using p53 as a keyword will find more than 100,000 articles.
In many tumors, p53 is an oncogene with a wide range of powerful functions and is known as the "guardian of the genome". p53 is activated in response to various cellular stressors (e.g., DNA damage). p53 activation promotes DNA repair or the controlled death of aberrant cells, which prevents the onset and progression of cancer. and progression. As a result, mutations in the p53 gene are very common in many cancers, and about half of all cancer patients carry a mutation in the p53 gene. p53 mutations are an important driver of cancer development, progression, treatment resistance, and poor prognosis.
And for the first time, a new study has found that the p53 protein is also directly linked to autism-like behaviors.
On September 28, 2023, Nianpei Tsai's team at the University of Illinois at Urbana-Champaign published an article in the journal Molecular Psychiatry titled: Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior, and hippocampus-dependent learning.
The study found that the p53 protein is critical for regulating social competence, repetitive behavior, and hippocampus-related learning and memory in mice, elucidating the relationship between the TP53 gene, which encodes the p53 protein, and neurodevelopmental and psychiatric disorders such as autism.
Synaptic enhancement underlies multiple forms of behavior and relies on the regulation of multiple activity-dependent transcription factors to orchestrate the expression of genes required to maintain synaptic transmission. And this latest study shows that the tumor suppressor p53 is a new transcription factor involved in this process.
The team first found that p53 can be elevated in cultured primary neurons by cLTP. By knocking down p53 in neurons, the team further found that p53 is required for cLTP-induced elevation of GluA1 and GluA2 subunits on the surface of the AMPA receptor (AMPAR). The AMPA receptor mediates rapid excitatory synaptic transmission in the CNS, and its dynamic expression in the post-synaptic membrane is associated with the induction and Its dynamic expression in the postsynaptic membrane is related to the induction and maintenance of LTP and LTD and is involved in the regulation of learning and memory activities.
Since LTP is one of the major plasticity mechanisms behind behavior, the research team used forebrain-specific p53 knockdown to assess the role of p53 in behavior. The findings suggest that while knocking down p53 in mice does not alter motor or anxiety-like behaviors, it significantly promotes repetitive behaviors and reduces socialization in both male and female mice. In addition, knockdown of p53 also impaired LTP in the hippocampus and hippocampus-dependent learning and memory.
Most importantly, these learning-related deficits were more pronounced in male than female mice, suggesting a sex-specific role for p53 in these behaviors. Using RNA sequencing (RNAseq) to identify p53-related genes in the hippocampus, the team found that knocking down p53 upregulated or downregulated several genes with known functions in synaptic plasticity and neurodevelopment.
Overall, this study demonstrates that p53 is an activity-dependent transcription factor that mediates the surface expression of AMPA receptors, permits hippocampal synaptic plasticity, suppresses autism-like behaviors, and promotes hippocampus-dependent learning and memory.