A National Eye Institute-funded research team at the University of Minnesota Medical School 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-central nervous system (CNS) barriers serve as a protective boundary between the bloodstream and the CNS by regulating transport of nutrients, hormones and metabolic waste. The barriers prevent swelling of the eye and the brain and also support their immune privilege. 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.
The researchers studied gene expression in the endothelial cells of mice to investigate the interplay between p53 and its negative regulator MDM2 and norrin/frizzled4 signaling.
"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, Ph.D., 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 that 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.
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