Heads of Laboratories
Cell death plays an important role in sculpting a developing organism and eliminating unwanted and potentially dangerous cells throughout life. All animal cells have a genetic program that, when activated, leads to a distinct form of cell death called apoptosis. Dr. Steller’s research focuses on how this death program is regulated by different signaling pathways and how abnormal regulation of apoptosis contributes to a variety of human diseases, including cancer.
Because apoptosis is central to both development and tissue homeostasis and is intimately associated with a variety of human diseases including cancer, autoimmunity, AIDS, neurodegenerative disorders and liver diseases, cell death proteins are promising drug targets. Using both Drosophila melanogaster and mice as model organisms, Dr. Steller’s laboratory investigates the molecular mechanisms that govern the decision between cell death and survival.
Apoptosis has been conserved in evolution from worms to insects to humans. Dr. Steller’s lab discovered and characterized a family of proteins that act as integrators of many different signaling pathways to ensure that the death program is activated in cells that are doomed to die. 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. In this way, Reaper-family proteins remove powerful “brakes” on death. A conserved IAP-binding motif that was originally discovered in these proteins has provided the basis for developing a novel class of cancer therapeutics that are currently being evaluated in clinical trials.
Many organs and tissues can repair wounds and regenerate cells that have been lost upon injury. Dr. Steller discovered that cells undergoing apoptosis in response to stress or injury (such as radiation) can stimulate their own replacement by secreting mitogens to induce proliferation of adjacent progenitor cells. These secreted mitogens include Wingless (Wnt) and BMP/TGF-β family proteins. These pathways have been highly conserved in evolution, and similar phenomena have been recently observed in mammals. These findings have 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. Dr. Steller’s work initially revealed the importance of this process for the generation of mature sperm, but subsequently similar mechanisms were shown to operate during development of the nervous system. Dr. Steller defined the role of enzymes that control protein degradation in this system, and he recently discovered a new mechanism for regulating the activity of proteasomes, the proteolytic complex responsible for the degradation of most intracellular proteins. Collectively this work reveals that the two major proteolytic systems, caspases and proteasomes, are coordinated to achieve “controlled demolition” of unwanted cellular structures. These findings are relevant for a better understanding and treatment of human diseases, including muscle-wasting diseases and cancer.
The Steller lab also studies cells that are highly resistant to cell death, including terminally differentiated neurons. Using Drosophila photoreceptor neurons as a model system, Dr. Steller is researching the survival mechanisms by which these cells resist apoptosis: One involves the unfolded protein response, which has been linked to diabetes, cancer and neurodegenerative diseases. However, Dr. Steller’s lab has shown that in a Drosophila model of autosomal dominant retinitis pigmentosa, a disease that causes blindness, the unfolded protein response is initiated in the endoplasmic reticulum organelle, not the cytoplasm, and protects cells from apoptosis. This research has added another level of complexity to the role of unfolded proteins in cell death and disease.
While Dr. Steller uses Drosophila as the primary model to discover cell death genes and order them into pathways, his lab is also testing whether concepts originally developed in Drosophila can be applied to mammalian systems and translated to the clinic. For this purpose, Dr. Steller and his colleagues have generated mouse strains with mutations in select cell death genes. This work has provided the first direct evidence for a role of mammalian IAP antagonists in caspase regulation and tumor suppression in vivo. Finally, Dr. Steller’s laboratory is developing small-molecule compounds that are designed to selectively activate apoptosis in cancer cells for highly specific and efficient tumor cell killing.
Born in Germany, Dr. Steller received his undergraduate degree in microbiology and molecular genetics from the University of Frankfurt in 1981. At the European Molecular Biology Laboratory and the University of Heidelberg, he earned his Ph.D. in molecular biology in 1984. After a postdoc in molecular neurobiology at the University of California, Berkeley, Dr. Steller became assistant professor of neurobiology at the Massachusetts Institute of Technology in 1987. He became associate professor in 1993, received tenure in 1994 and became professor in 1996. Dr. Steller came to Rockefeller in 2000.
In 2001 Dr. Steller received the Lady Davis Award from the Faculty of Medicine, Technion-Israel Institute of Technology. He was named a Pew Scholar by the Pew Charitable Trusts in 1989 and a Searle Scholar by the Chicago Community Trust in 1988.
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