Arbeitsgruppe Malek
Research: Control of Cell Division
Our lab is interested in understanding basic mechanisms of cell division specifically with regard to tumor-development and organ regeneration.
We are focusing our studies on the control of proteins which activate or inactivate the basic machinery that controls the decision to enter the cell cycle. Central components of this process are the cyclins and the cyclin dependent kinases. Activation of cyclins in concert with their associated kinase activity induces cellular changes which ultimately lead to cell division. Therefore the activity of these proteins must be tightly controlled which is achieved through multiple different mechanisms including binding to so called cyclin kinase inhibitors.
One of these proteins, p27kip1, is a direct inhibitor of cdk2 associated kinase activity. This central function in the cell cycle makes p27 an important regulator of G1 phase progression. In the past we and others showed that the stability of the cyclin kinase inhibitor p27 is regulated by phosphorylation dependent ubiquitylation. We showed that this process is part of the progression sequence of intestinal cancers using a mouse model in whch p27 turnover is impaired. We also showed that the F-Box protein skp2 which is part of a so called E3 ubiquitin ligase complex regulates p27 degradation in vivo thereby controlling cellular growth and division. Recently we identified a novel mechanism by which multiple functions of p27 are regulated through phosphorylation at a conserved threonine.
Current Projects
1. Cell Cycle control
We are continuing to study the function and regulation of p27 and Cyclin E using a combination of molecular biology, biochemistry and mouse models. We are particularly interested in mechanisms which regulate the proliferation of liver cells specifically with regard to the development of hepatocellular carcinomas. We are also studying ways to expand liver cells in vitro as a resource for liver cell transplantation.
2. Role of proteolytic processes in the control of cellular homeostasis
Based on our previous work on the F-box protein skp2 we are studying the role of controlled protein degradation for the maintainance of cellular homeostasis. We are particularly interested to understand how different proteolytic complexes interact to ensure that cells remain genetically stable.
We are currently developing mouse models with defects in certain genes involved in proteolytic processing of cell cycle regulators. We will use these systems to understand the function of regulated proteolysis under conditions of organ regeneration and tumorigenesis.
3. Drug development/Translational Research
Given the enormous importance of proteins involved in cell cycle regulation for the development of cancer we have started to use high throughput technology to identify substances which are able to influence the activity or stability of cell cycle regulators. This aspect of our work is done in close collaboration with the Helmholtz Center for Infectious Disease in Braunschweig and the Leibniz University Hannover.
