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Cell death plays an important role in sculpting a developing organism, and in eliminating unwanted and potentially dangerous cells throughout life. Steller’s research focuses on how programmed cell death is regulated and how its dysfunction contributes to disease, including cancer. He also studies the nonlethal use of cell death proteins for cellular remodeling and the mechanism of protein degradation in development, aging, and disease.

Central to both development and tissue homeostasis, apoptosis is intimately associated with a variety of human diseases including cancer, autoimmunity, AIDS, neurodegenerative disorders, and liver diseases. This makes cell death proteins promising drug targets. Using both Drosophila melanogaster and mice as model organisms, Steller’s lab investigates the molecular mechanisms that govern the decision between cell death and survival.

Apoptosis has been conserved throughout evolution, from worms to insects to humans. Steller’s team discovered and characterized a family of proteins that act as integrators of many different signaling pathways to ensure that the death program is activated. Reaper, Hid, and Grim activate apoptosis by binding to and inactivating inhibitor of apoptosis (IAP) proteins, which in turn directly inhibit caspases, the key executioners of apoptosis. A conserved IAP-binding motif originally discovered in these proteins has provided the basis for a novel class of cancer therapeutics currently in clinical trials.

Many organs and tissues can repair wounds and regenerate cells lost upon injury. Steller discovered that cells undergoing apoptosis in response to stress or injury can stimulate their own replacement by secreting mitogens to induce proliferation of adjacent progenitor cells. These mitogen pathways have been highly conserved throughout evolution, and similar phenomena have been observed in mammals with profound implications for cancer therapy, stem cell biology, and regenerative medicine.

The cell death machinery can also serve nonlethal functions for cellular remodeling in Drosophila and mammals. Steller’s work initially revealed the importance of this process for the generation of mature sperm. Subsequently, similar mechanisms were shown to operate during nervous system development. Steller defined the role of enzymes that control protein degradation by the apoptosis machinery, and his work has revealed that two major proteolytic systems, caspases and proteasomes, are coordinated to achieve “controlled demolition” of unwanted cellular structures. These findings are relevant for human diseases, including muscle-wasting diseases, neuronal degeneration, and cancer.

More recently, work in Steller’s lab has focused on the mechanisms by which cells degrade unwanted or toxic proteins. The long-term health of cells critically relies on selective protein degradation since damaged or aggregated proteins cause proteotoxic stress that can impair cell function and cause cell death. Many neurodegenerative diseases—including Alzheimer’s, Parkinson’s, Huntington’s, ALS, and retinitis pigmentosa—are caused by the accumulation of protein aggregates. Steller and his colleagues discovered a mechanism that enables cells to boost their proteolytic capacity by stimulating the assembly of proteasomes, the multi-protein protease complex responsible for the regulated degradation of intracellular proteins. Manipulating the activity of this pathway may lead to novel therapeutics for the treatment of age-related neurodegenerative diseases.