Summary: Researchers have uncovered a surprising connection between a cancer-related signaling pathway and the blood-brain and blood-retina barriers. The study shows that the tumor-suppressing protein p53 weakens the Norrin/Frizzled4 pathway, which is crucial for maintaining these protective barriers.
This suggests that cancer therapies boosting p53 might unintentionally compromise brain and eye vascular integrity. The findings also spotlight NCAPH as a potential gene involved in inherited retinal disease and vascular disorders.
Key Facts:
- Barrier Vulnerability: Increasing p53 levels can impair the blood-brain and blood-retina barriers by disrupting Norrin/Frizzled4 signaling.
- Therapy Risks: MDM2 inhibitors, designed to raise p53 for cancer treatment, may cause neuroinflammation and vascular dysfunction.
- Disease Gene: NCAPH emerges as a potential contributor to familial exudative vitreoretinopathy and other vascular diseases.
Source: University of Minnesota
A University of Minnesota Medical School-led research team discovered that a cancer signaling pathway has previously unrecognized roles in retina and brain blood vessels.
The findings were recently published in Science Signaling.
Blood-CNS barriers serve as a protective boundary between the bloodstream and the central nervous system by regulating transport of nutrients, hormones and metabolic waste and preventing retinal and brain swelling.
One of the key mediators of this mechanism is the Norrin/Frizzled4 signaling pathway. Until now, the link between this pathway and the MDM2–p53 axis — which suppresses tumors — had not been recognized.
“Our findings reveal an unexpected link between the p53 stress response pathway and Norrin signaling in the vasculature of the central nervous system,” said Harald Junge, PhD, an associate professor at the University of Minnesota Medical School.
“This has implications for cancer treatments that target MDM2 and increase p53 abundance. It’s important to consider that these treatments could impact barrier function, which could potentially lead to dysregulated transport between blood and CNS, neuroinflammation and swelling.”
The study found that p53 — a protein known for protecting against cancer — weakens the Norrin/Frizzled4 signaling system in blood vessels by lowering levels of another protein called NCAPH. These findings suggest drugs that boost p53 levels — such as MDM2 inhibitors — may accidentally damage the protective barriers in the brain and eyes.
The study also highlights NCAPH as a new candidate gene linked to familial exudative vitreoretinopathy (FEVR) — a rare, inherited eye condition that affects blood vessel growth in the retina.
Given the critical role of p53 in regulating vascular barrier function, it is important to evaluate whether MDM2 inhibitors — currently in clinical testing for cancer — could adversely affect the blood-retina or blood-brain barriers.
The findings also support further investigation into the role of NCAPH in endothelial cells, both as a downstream effector of p53 and as a potential disease gene in vascular disorders like FEVR.
Funding: This study was supported by grants from the National Eye Institute and National Institutes of Health [R01EY024261, R01EY033316 and 1R21DA056728-01A1].
About this brain cancer research news
Author: Alexandra Smith
Source: University of Minnesota
Contact: Alexandra Smith – University of Minnesota
Image: The image is credited to Neuroscience News
Original Research: Open access.
“The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function” by Harald Junge et al. Science Signaling
Abstract
The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function
Norrin-induced activation of β-catenin–dependent signaling through the receptor frizzled4 in endothelial cells (ECs) is essential for establishing and maintaining blood-CNS barrier function.
We sought to determine how this pathway is modulated under stress or disease conditions. Specifically, we investigated the role of p53 in endothelial blood-CNS barriers because increased abundance of the transcription factor p53 in ECs correlates with leaky CNS blood vessels in type 2 diabetes.
Using transcriptomic, cell-based, and mouse genetic approaches, we identified interplay between p53 and its negative regulator MDM2 and norrin/frizzled4 signaling.
Mice with an EC-specific ablation of Mdm2 showed decreased norrin/frizzled4 signaling, reduced EC proliferation and retinal angiogenesis, and disrupted blood-retina barrier function, all of which were largely restored by concurrent Trp53 deletion.
Decreased norrin/frizzled4 signaling and inhibition of EC proliferation in response to p53 were associated with reduced expression of the condensin I complex component non-SMC condensin I complex subunit H (NCAPH).
This study identifies a regulator of norrin/frizzled4 signaling and suggests that the clinical use of MDM2 inhibitors might impair the blood-CNS barrier.
In addition, NCAPH may be a downstream effector of p53 in ECs and a candidate gene for familial exudative vitreoretinopathy (FEVR), which is caused by defects in norrin signaling.
