Environmental Factor, June 2007, National Institute of Environmental Health Sciences
Distinguished Lecturer Reports on Coactivator Research
By Eddy Ball
The 2006-2007 Distinguished Lecture Series concluded on May 22 in Rodbell Auditorium with a talk by Bert W. O'Malley, M.D. O'Malley is a professor and chairman of the Department of Molecular and Cellular Biology at the Baylor College of Medicine. His lecture was titled "The Expanding Roles of Nuclear Factor Coactivators."
When he introduced O'Malley as the final speaker in this year's lecture series, Host John Cidlowski, Ph.D., commented, "I think it's clear we've saved the best for last." Widely recognized as a pioneer in the field, O'Malley has studied steroid hormone action for over 30 years and published over 750 manuscripts. "In my opinion," Cidlowski continued, "he's probably done the most creative work of anyone in the field."
O'Malley had come to NIEHS to discuss his latest discoveries about the role of coactivators identified for nuclear receptors (NRs) in gene transcription.
He said that nearly 300 coactivators and some 65 corepressors have been discovered so far in ongoing efforts to break the "coactivator code."
NRs are transcription factors that play essential roles in a wide range of biological processes. These processes include the disrupted lipid and energy metabolism linked to development of the chronic conditions that plague increasing numbers of people, such as diabetes and obesity, as well as hormone-stimulated cancers of the breast, prostate and ovaries.
Coactivators contribute to the transcriptional process through enzymatic activities, such as acetylation, methylation, ubiquitination and phosphorylation, and through chromatin remodeling. In orderly cell regulation, coactivator complexes work in concert with corepressors to maintain a balance between transcription events, post-translational modifications and the disassembly of the complex.
These multiprotein complexes of activators and repressors define the type and extent of an organism's response to NR molecular binding and whether specific genes are expressed as proteins. "There's a sophisticated coding here," O'Malley explained, "[that] determines the collection of proteins that will form the active complex in the nucleus."
In the course of his talk, O'Malley concentrated primarily on a powerful cancer-promoting gene called steroid receptor coactivator (SRC)-3, which he described as "a master gene for cellular growth." When SRC-3 is insufficiently balanced by levels of a little known protein called REG-gamma, SEC-3 promotes continuing cell replication. "Tumors love SRC-3," he observed, "especially breast cancer... A tumor has a great advantage if it can increase the levels of this protein."
O'Malley repeatedly used the word "complexity" as he talked about coactivator codes. He expects that more coactivators will be discovered. Many may turn out to be "molecules with many faces" that exhibit the same kind of contradictory actions as SRC-3, which can function as a cancer promoter or a cancer repressor. O'Malley also anticipates that eventually researchers will be able to describe the different combinations of factors that determine activation codes, death codes and transcriptional time clocks governing biological processes at the cellular level.
A better understanding of these complexes will ultimately lead to therapeutic applications, O'Malley concluded. "These have been associated with 163 human diseases," he said. "They're going to be big in disease, which means they'll also be big in pharmacology when we learn how to manipulate them."
(Note: O'Malley is a co-director of the Nuclear Receptor Signaling Atlas, a trans-NIH consortium, and a major contributor to educational material about nuclear receptor signaling available on the organization's website(https://www.nursa.org/nursa/index.jsf .)