The Guardian of the Genome – the role of P53 in Cancer Prevention and in increasing/decreasing Autistic Behaviors

 

The p53 protein is called the guardian of the genome because it plays a critical role in maintaining genomic stability. It does this by surveying the genome for signs of DNA damage. If p53 detects DNA damage, it activates a number of different cellular responses to prevent the damaged cell from dividing and passing on that damage. These responses can include:

• p53 can halt the cell cycle giving the cell time to repair the damaged DNA.
• p53 can activate genes that are involved in DNA repair.
• If the DNA damage cannot be repaired, p53 can trigger cell death.

p53 protects your genome by preventing damaged cells from dividing and passing on DNA damage.

 

What about p53 and autism?

We have seen many times that cancer genes overlap with autism genes; that is the case today with p53. The protein p53 acts like a transcription factor turning on or off key genes in the brain that affect learning and behavior. 

Protein p53’s Role in Autism-like Behavior and Memory

Scientists have discovered a direct link between the protein p53 and autism-like behavior in mice. The researchers studied the effects of manipulating p53 levels in the mouse hippocampus.

Reduced levels resulted in repetitive behavior, diminished sociability, and impaired learning, especially in male mice. This pivotal work uncovers the intricate role of p53 in neurodevelopmental disorders like autism.

Key Facts:

1.     Lowered hippocampal p53 levels in mice led to repetitive behavior, decreased sociability, and hindered hippocampus-dependent learning.

2.     Elevated p53 levels were observed during periods of enhanced communication between hippocampal neurons, related to positive learning outcomes.

3.     Previous research from 2018 identified p53’s significant role in irregular brain cell activity seen in both ASD and epilepsy.

 

In this study, Tsai and his colleagues lowered hippocampal p53 levels in mice, looking for changes in gene expressions related to behavior. They observed that the decreased p53 levels: 

·        Promoted repetitive behavior in mice.

·        Reduced sociability in mice.

·        Impaired hippocampus-dependent learning and memory, especially in male mice.

The researchers also observed that p53 levels were elevated after a period of active communication between hippocampal neurons called long-term potentiation. Flexible neuron firing — known as plasticity — is related to positive learning and memory outcomes. 

In a 2018 study, Tsai and his colleagues identified p53 as a key protein involved in the irregular brain cell activity seen in ASD and epilepsy. In future studies, they aim to explore how p53 coordinates the expression of those autism-linked genes to guide behavior. 

 

The full paper: 

Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior and hippocampus-dependent learning

Synaptic potentiation underlies various forms of behavior and depends on modulation by multiple activity-dependent transcription factors to coordinate the expression of genes necessary for sustaining synaptic transmission. Our current study identified the tumor suppressor p53 as a novel transcription factor involved in this process. We first revealed that p53 could be elevated upon chemically induced long-term potentiation (cLTP) in cultured primary neurons. By knocking down p53 in neurons, we further showed that p53 is required for cLTP-induced elevation of surface GluA1 and GluA2 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Because LTP is one of the principal plasticity mechanisms underlying behaviors, we employed forebrain-specific knockdown of p53 to evaluate the role of p53 in behavior. Our results showed that, while knocking down p53 in mice does not alter locomotion or anxiety-like behavior, it significantly promotes repetitive behavior and reduces sociability in mice of both sexes. In addition, knocking down p53 also impairs hippocampal LTP and hippocampus-dependent learning and memory. Most importantly, these learning-associated defects are more pronounced in male mice than in female mice, suggesting a sex-specific role of p53 in these behaviors. Using RNA sequencing (RNAseq) to identify p53-associated genes in the hippocampus, we showed that knocking down p53 up- or down-regulates multiple genes with known functions in synaptic plasticity and neurodevelopment. 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.

  

How to upregulate p53?

It is important to note that increasing p53 levels does not guarantee that p53 will be activated.

Researchers are still in the early stages of developing drugs that can specifically activate p53.

There are a number of food products that have been shown to increase p53 levels in cells, such as cruciferous vegetables like broccoli.

If you refer to the excellent Gene Cards resource, you will find that very many drugs can help activate p53. Almost 500 are listed – too many for me to review here.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=TP53

 

One example is the old antihistamine Clemastine that has been recommended in this blog, for completely different reasons. A paper in 2023 suggests “Repurposing Clemastine to Target Glioblastoma (brain cancer)”.

Indole-3-carbinol (I3C) gets listed as does Epigallocatechin gallate (EGCG).

I have mentioned previously that I3C is one reason (unrelated to sulforaphane) that broccoli can be beneficial in some autism.

The last time I mentioned EGCG, a catechin found in green tea, a doctor reader contacted me to tell me that he has taken it for 20 years for its antiangiogenic properties. Antiangiogenic means that something prevents or slows down the growth of new blood vessels. Cancer cells need a blood supply to grow and spread. They produce proteins called angiogenic factors, which stimulate the growth of new blood vessels. Antiangiogenic drugs work by blocking the effects of angiogenic factors or by targeting the cells that produce them. This can starve cancer cells of the blood they need to grow and spread.  It seems to have worked well for our reader!

We have seen that EGCG has been proposed to treat girls with Rett syndrome.

EGCG has been shown to have a number of beneficial effects in cells and animal models of Rett syndrome. For example, EGCG has been shown to: 

·        Increase levels of the p53 tumor suppressor protein

·        Reduce oxidative stress

·        Improve mitochondrial function

·        Promote synaptic plasticity

·        Protect neurons from damage

One of our readers finds that Broccoli powder (Broccomax) provides a boost to his daughter with Rett syndrome. Is it the sulforaphane or it the Indole-3-carbinol (I3C)? My bet would be on the I3C from the broccoli.  You can buy I3C itself.

 

Conclusion

More p53 please!

Eating well is much more than just about vitamins.  Eating all those healthy foods mentioned above that many people avoid will boost your p53 levels.

Ultimately there will be an expensive new drug to boost p53 in cancer patients.

Very many old drugs do have secondary effects that include boosting or activating p53.

Curcumin, not surprisingly, boosts p53 and helps protect people of Indian origin from cancer via their traditional diet.

Genistein, resveratrol, EGCG, broccoli powder are all supplements that boost p53.

It is nice to see that Clemastine, my favorite old antihistamine that may promote myelination in some, stabilize activated microglia in some, many also increase p53 sufficiently to be seen as a potential anti-cancer therapy.

Maybe keep an eye out for Dr Tsai, particularly if you are interested in Fragile X or p53. Here he is: 

https://mcb.illinois.edu/directory/profile/nptsai