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St. Jude Researchers Find Key Step in Programmed Cell Death
Date:2/29/2008

long studied how cytokines--small proteins used by neurons and blood-borne cells to communicate messages--contribute to keeping cells alive. For example, they demonstrated earlier that most cytokines controlling hematopoietic cells require an enzyme called Jak2, or Jak3 in lymphocytes, at the receptors where cytokines attached to the cell.

In screening for components that are regulated by the Jak enzymes, the St. Jude team found the Hax1 protein.

"That was intriguing because several studies suggested that Hax1 was controlled by cytokine signaling," Ihle said. "Also, studies have suggested that if you overexpressed Hax1 in cells, the cells were protected from undergoing apoptosis."

To pursue this lead, the researchers genetically engineered mice that lacked the gene for Hax1. The results showed that apoptosis in the animals' brain caused extensive nerve cell degeneration that killed the mice within 10 to 12 weeks. Second, apoptosis in immune-system lymphocytes occurred in the altered mice eight hours sooner than in those with the Hax1 gene, when limited amounts of cytokines were available.

"That additional window of survival is extremely important because in the body, cytokines are limiting." Ihle said. "The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl."

Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria--tiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cell's cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins. The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions Ht
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SOURCE St. Jude Children's Research Hospital
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