National Science Foundation (NSF)-funded researchers at the Johns Hopkins School of Medicine in Baltimore, Maryland, and at California's Stanford University have shed new light on the molecular switches that control the complex process by which a single fertilized egg develops into a mature organism. Their paper is published in the February 19, 1999, issue of the journal Cell.
In humans and other mammals, the process is orchestrated in the developing embryo by a set of proteins called "Hox proteins" that control the timely expression of genes -- and thereby control the production of the "next stage" proteins needed for embryonic development. The action of Hox proteins must, in turn, be coordinated to assure the accurate development of an embryo; that coordination involves another set of proteins that act as molecular choreographers.
"Failure of the molecular systems that control development prevents normal embryonic growth, and alterations in these control systems can lead to a wide variety of cancers," explains Kamal Shukla, program director in NSF's division of cellular and molecular biosciences, which funds the research. "Understanding the molecular mechanisms that control normal embryonic development is the first step in developing strategies to prevent these errors, or to repair them when they have gone wrong." Cynthia Wolberger at Johns Hopkins and Michael Cleary at Stanford have made a major step forward in the understanding of these crucial molecular events, Shukla believes.
This research, which uses x-ray crystallography, has led to the determination of the atomic structure of "HoxB1" and a protein called Pbx1, all bound to a fragment of DNA. Pbx1 plays a central role in the modulation of Hox protein function, and mutations in it have been implicated in some childhood leukemias. By visualizing how Pbx1 interacts with a Hox protein and with DNA, Wolberger and colleagues have determined the precise way in which the proteins interact with one another to control development.
Pbx1, by interacting with Hox proteins, is able to control the expression of many different types of proteins, says Wolberger. "Understanding how they interact with partner proteins such as Pbx1 and with DNA is key to knowledge of the mechanism by which a developing organism grows from a single fertilized egg cell into a fully differentiated creature with head and tail, arms and legs."
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