Most commonly mutated gene in cancer `may play role in stroke`

Researchers have found that the gene p53, which is the most commonly mutated gene in cancer, has a novel role in the development of ischemic stroke. p53 is dubbed the “guardian of the genome” because it blocks cells with damaged DNA from propagating and eventually becoming cancerous. However, new research led by Ute M. Moll, M.D., Professor of Pathology at Stony Brook University School of Medicine, and colleagues, uncovers a novel role for p53 beyond cancer in the development of ischemic stroke. The team identified an unexpected critical function of p53 in activating necrosis, an irreversible form of tissue death, triggered during oxidative stress and ischemia. Ischemia-associated oxidative damage leads to irreversible necrosis which is a major cause of catastrophic tissue loss. Elucidating its signalling mechanism is of paramount importance. p53 is a central cellular stress sensor that responds to multiple insults including oxidative stress and is known to orchestrate apoptotic and autophagic types of cell death. However, it was previously unknown whether p53 can also activate oxidative stress-induced necrosis, a regulated form of cell death that depends on the mitochondrial permeability transition pore (PTP) pore. “We identified an unexpected and critical function of p53 in activating necrosis: In response to oxidative stress in normal healthy cells, p53 accumulates in the mitochondrial matrix and triggers the opening of the PTP pore at the inner mitochondrial membrane, leading to collapse of the electrochemical gradient and cell necrosis,” Moll said. “p53 acts via physical interaction with the critical PTP regulator Cyclophylin D (CypD). This p53 action occurs in cultured cells and in ischemic stroke in mice,” Moll said. They found in their model that when the destructive p53-CypD complex is blocked from forming by using Cyclosporine-A type inhibitors, the brain tissue is strongly protected from necrosis and stroke is prevented. “The findings fundamentally expand our understanding of p53-mediated cell death networks. “The data also suggest that acute temporary blockade of the destructive p53-CypD complex with clinically well-tolerated Cyclosporine A-type inhibitors may lead to a therapeutic strategy to limit the extent of an ischemic stroke in patients,” Moll said. Yusuf A. Hannun, M.D., Director of the Stony Brook University Cancer Center, also commented on the role of p53. “p53 is one of the most important genes in cancer and by far the most studied,” Hannun said. “Therefore, this discovery by Dr. Moll and her colleagues in defining the mechanism of a new p53 function and its importance in necrotic injury and stoke is truly spectacular,” he added. The study has been published online in Cell.