May 18, 2004 SALT LAKE CITY –- In what may be the cellular equivalent of watching the Grim Reaper in action, University of Utah School of Medicine researchers have shown that two "death activator" genes are essential for cell death when Drosophila (fruit flies) metamorphose from larvae to adults. Death of obsolete larval tissue is critical in insect metamorphosis.
The two genes--reaper (rpr) and hid (head involution defective)--act by overcoming the protective efforts of a death inhibitor, DIAP1. Once DIAP1 is disabled, the inexorable begins and larval tissues like the salivary glands are rapidly destroyed, according to Carl S. Thummel, Ph.D., professor of human genetics at the Eccles Institute of Human Genetics, and doctoral student Viravuth P. Yin. The two will publish their findings in the May 25 print edition of the Proceedings of the National Academy of Sciences. The article will appear online the week of May 17.
"They are true (cell) death genes in Drosophila that are critical for the destruction of larval tissue during metamorphosis," Thummel said.
The finding opens the possibility that someday death-inducing genes could be unloosed to specifically kill unwanted cells--such as tumors.
Cell death (apoptosis) begins when ecdysone, a steroid hormone, binds to its receptor, EcR/USP. This binding allows the receptor to activate three key regulatory genes--E93, BR-C, and E74A. Those genes turn on reaper and hid, which then deactivate the death inhibitor DIAP1. When DIAP1 is no longer functioning, cell death is unleashed in the salivary glands, leading to the destruction of larval tissue and their replacement by adult structures.
Ecdysone already was known to regulate a number of genes; and reaper and hid were known as death activators. But it had not been proved that those two genes are essential for salivary gland cell death to occur, and no roles were known for DIAP1 in preventing premature larval cell death. Ecdysone is the critical signal in starting the process, according to Thummel.
"This hormone (ecdysone) is the trigger that changes Drosophila from its larval to adult form," he said.
To identify roles for reaper and hid in cell death, Yin and Thummel used a combination of genetic tools to reduce their function. This allowed them to determine how the two genes influenced cell death in Drosophila larvae. When hid was removed from the process, salivary gland death was partially blocked. Both reaper and hid had to be inactivated before Yin saw a complete block in cell death, leading to the conclusion that both genes are required for efficient larval tissue cell death.
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