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Molecule acts as umpire to make tough life-or-death calls
Date:5/22/2014

we might be able to develop cancer therapies that target these the pathways or engage them in other ways to advance treatment of a range of diseases."

The study is one of two involving RIPK1 being published in the same edition of Cell.

The St. Jude report builds on previous research from Green's laboratory regarding regulation of the pathways that control two types of programmed cell death. One, called apoptosis, is driven by an enzyme named caspase-8. It forms a complex with a protein named FADD as well as other proteins that prompt cells to bundle themselves into neat packages for disposal. The other, called necroptosis, involves a different pathway that is orchestrated by the enzyme receptor-interacting protein kinase 3 (RIPK3). Researchers knew that before birth, RIPK1 worked through RIPK3 to trigger cell death by necroptosis, but until now the enzyme's primary role after birth was uncertain.

For this study, researchers bred mice lacking different combinations of genes for ripk1, ripk3, caspase-8, FADD and other components of both the apoptotic and necroptotic pathways.

Mice lacking ripk1 died. Mice missing two genes ripk1 plus ripk3 or ripk1 plus caspase-8 or FADD also died soon after birth. Mice survived and developed normally, however, when researchers removed three genes ripk1, ripk3 and either caspase-8 or FADD. "The fact that the mice survived was totally unexpected and made us rethink how these pathways worked," Green said.

Added Christopher Dillon, Ph.D., a postdoctoral fellow in Green's laboratory: "Knocking out two genes to restore balance following the loss of another gene, in this case RIPK1, is exceedingly rare." Dillon and St. Jude postdoctoral fellows Ricardo Weinlich, Ph.D., and Diego Rodriguez, Ph.D., are the paper's first authors.

The finding established RIPK1's premier role in cell survival as inhibition of apoptosis and necroptosis.

The results also demonstrated th
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Contact: Carrie Strehlau
carrie.strehlau@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

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