Receptors' response to hormones highlight Flexner lecture
Keith Yamamoto, Ph.D.
The intracellular receptors for hormones like testosterone and cortisol took center stage at the 1999 Abraham Flexner Lectures.
Keith R. Yamamoto, Ph.D., professor and chair of Cellular and Molecular Pharmacology at the University of California, San Francisco, described in molecular detail how these receptors respond to hormones, switching genes on and off.
Yamamoto presented structural data and described how the receptor protein changes shape when a hormone binds to it and when the hormone-receptor complex binds to DNA.
He also discussed the paradoxical actions of drugs that bind to receptors in this family. The anti-cancer drug tamoxifen, for example, blocks the estrogen receptor in breast cells, but activates the receptor in endometrium, bone, and liver.
In addition, whether the receptor turns genes on or off depends on the hormone or drug it binds with, on other proteins, and also on the type of cell. Yamamoto is investigating how these multiple factors influence the final signaling outcome.
"I want you to leave here with the message that you can't just look at a hormone, a receptor, a DNA sequence, or a cell type and automatically know what the activity will be," Yamamoto said. "Everything depends on the context."
At the conclusion of both of his lectures, Yamamoto proposed the existence of "phantom factors" – as yet undiscovered proteins that participate in intracellular receptor signaling.
"Since it isn't the receptor alone that determines how a drug works, we think there must be other proteins that influence whether the drug activates or blocks the receptor, and therefore, whether genes get turned on or off," Yamamoto said.
Yamamoto and his colleagues are searching for these factors, and they believe that the activities of such proteins might change in disease. For example, prostate cancer initially depends on androgen steroid hormones, but progresses to an androgen independent state.
Yamamoto is a member of the American Academy of Arts and Sciences and of the National Academy of Sciences. He serves as the Chairman of the Advisory Committee to the NIH Center for Scientific Review and is a member of the NIH Director's Peer Review Oversight Group. For his scientific achievements and national service, Dr. John E. Chapman, Dean of the School of Medicine, presented Yamamoto with the Vanderbilt Medal of Merit.
As the Flexner lecturer, Yamamoto joined a distinguished group.
"This is Vanderbilt's longest running and most prestigious lecture series," said Dr. Darryl K. Granner, professor of Molecular Physiology and Biophysics and director of the Vanderbilt Diabetes Center.
The lectureship has been endowed by the Flexner family since 1977. It was named for Dr. Abraham Flexner, the author of the Flexner Report, in recognition of his service to medical education. It is presented annually by the School of Medicine.