May 3, 2010 The reading of genes and the related procedure of producing cellular protein molecules are essential for the correct functioning of every cell. This process is called gene expression and is controlled by special protein molecules, so-called transcription factors. A change in these molecules is in most cases pathological, leading to diseases such as cancer.
A team of researchers led by Prof. Dr. Katja Arndt from the Institute of Biology III of the University of Freiburg has succeeded in constructing small protein fragments which can block the incorrectly regulated gene expression. In collaboration with a team headed by Andrew Woolley, professor at the University of Toronto, the scientists developed a mechanism which allows these inhibitors to be switched on and off like a light switch.
The findings have now been published in the journal Angewandte Chemie, whose editors have classified it as a "hot paper" due to its great significance for a rapidly developing area of research. The project was funded by the DAAD, the University of Freiburg's excellence cluster BIOSS (Centre for Biological Signalling Studies), and the FRIAS School of Life Sciences -- LifeNet.
The study described in the publication combines two independent developments: inhibitors constructed by Katja Arndt which regulate oncogenes (cancer genes), and chemical adapter molecules developed by Andrew Woolley's research group which can appear in two structural states depending on their wavelength. The chemical linkers can be coupled with the inhibitors and made to function like a light switch: In the lit state the inhibitor is „on" and thus active, and in the dark state the inhibitor is "off" and thus inactive. The researchers were able to control the activity of the oncogenic (cancer causing) transcription factor AP-1 (activator protein 1) using this switchable inhibitor. They discovered that even a basic condition for controlling gene expression can be controlled by light, namely the DNA binding process. The researchers were also able to switch the subsequent genes on and off by controlling the AP-1 transcription factor. By "turning on" the light they activated the inhibitor and blocked the expression, and by "turning off" the light they deactivated the inhibition.
The new technology has many potential areas of application. First of all, molecular light switches of this kind are interesting components for the switchboard of synthetic biology, a core element of BIOSS, because they make it easy to control synthetic signaling paths from outside. In addition, there are many potentially interesting uses for the newly developed light switches in systems biology. For example, they play a role in the investigation of temporally controlled biological processes, such as the appearance and recognition of anxiety. In medicine the light switches could be used as lead structures for new therapeutical approaches.
In addition to Prof. Dr. Katja Arndt and Prof. Dr. Andrew Woolley, Katharina Timm, doctoral student in the excellence cluster BIOSS, and Dr. Fuzhong Zhang from Andrew Wooley's group also participated in the study. Katja Arndt is a member of BIOSS and a junior fellow at the Freiburg Institute for Advanced Studies, research institute of the University of Freiburg. She also works at the Institute of Biology III and recently accepted a chair in molecular biotechnology at the University of Potsdam.
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- Fuzhong Zhang, Katharina A. Timm, Katja M. Arndt, G. Andrew Woolley. Photocontrol of Coiled-Coil Proteins in Living Cells. Angewandte Chemie International Edition, 2010; DOI: 10.1002/anie.201000909
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