The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. Lee E, Salic A, Kruger R, Heinrich R, and Kirschner MW, PLoS Biol.1(1): 2003.
In work led by Marc Kirschner at Harvard Medical School, the authors developed a mathematical model for the canonical Wnt pathway that describes the interactions among the core components: Wnt, Frizzled, Dishevelled, GSK3beta, APC, Axin, beta-catenin, and TCF. Using a system of differential equations, the model incorporates the kinetics of protein-protein interactions, protein synthesis/degradation, and phosphorylation/dephosphorylation. Predictions based on the analysis of the reference state were used iteratively to develop a more refined model that was used to analyze the effects of prolonged and transient Wnt stimulation on beta-catenin and Axin turnover. An insight from the model, confirmed experimentally, is that the two scaffold proteins Axin and APC promote the formation of degradation complexes in very different ways.
This paper demonstrates concretely the power of a multidisciplinary approach and will become a forerunner of a framework that will be duplicated by others, says Bud Mishra, a computational biologist at New York University. The techniques that the researchers employed in the paper are based on ODE models, numerical integration, and direct comparison of numerical traces and time course data — which can all be carried out with existing scientific computational tools — but the work will influence, encourage, and inspire others to develop novel techniques to make better quantitative measurements and to rigorously analyze complex biological systems, he adds.
Professor of Cell Biology, Computer Science, and Mathematics
New York University
Regulation of gene expression by a metabolic enzyme. Hall D, Zhu H, Zhu X, Royce T, Gerstein M, Snyder M. Science 15 October 2004; 306: 482-484.
Using a yeast proteome microarray, Michael Snyder and his colleagues at Yale University have discovered that Arg5,6, a mitochondrial enzyme involved in arginine biosynthesis, has DNA binding activity. Chromatin immunoprecipitation experiments produced evidence that Arg5,6 is associated with specific nuclear and mitochontrial loci in vivo, and deletion of Arg5,6 causes altered transcript levels of both nuclear and mitochondrial target genes.
The work is significant because it is the first example of a metabolic enzyme directly regulating eukaryotic gene expression, says Jeff Skolnick, director of the Buffalo Center For Excellence in Bioinformatics at the University at Buffalo. Gene products with enzymatic and structural functions are known to regulate gene expression indirectly, but until now it wasn’t clear how important a regulatory role they play. The research is also notable because it relies — at least in part — on the yeast proteome array, a relatively new tool developed in Snyder’s lab for probing protein function.
Director, Buffalo Center for Excellence in Bioinformatics
University at Buffalo
The State University of New York
Dynamics of cellular level function and regulation derived from murine expression array data. de Bivort B, Huang S, Bar-Yam Y. Proc Natl Acad Sci U S A. 2004 Dec 21;101(51)17687-17692.
In contrast to most experimental work investigating regulatory mechanisms in small networks of genes, Yaneer Bar-Yam at Harvard University and his co-authors chose a larger-scale study in an effort to observe the cumulative effects of all gene interactions in terms of cellular-level function. By organizing groups of genes into large groups with related behaviors, called megamodules, the authors were able to determine the effective aggregate regulatory influences among 12 major gene groups in murine B lymphocytes over a variety of time steps, as they write in the abstract.
Applying systems biology to humans and mice is typically slow and expensive, but Bar-Yam and his co-authors overcome cost and complexity issues by reducing complex data into smaller numbers of profiles and identifying the interactions between these profiles, says Toshimori Kitami, a biologist at Case Western Reserve University. While this method may omit some details, it provides a stepping ground for more feasible systems biology research in higher eukaryotes, Kitami adds.
Graduate Student, Department of Genetics
Case Western Reserve University
Peer Review is a forum for scientists to recommend noteworthy recent papers. If you have a recommendation, e-mail it to John MacNeil at [email protected]