Aim of the project
This MSc project is part of a larger project where we both use established and test new methods to inhibit formation of ErbB2-Cdc37-Hsp90 complex and in detail characterize the molecular mechanisms leading to endocytic down-regulation of ErbB2. The results from this study will give important new basic knowledge on how ErbB2 is controlled, knowledge that may lead to improved treatment of cancers showing altered expression of ErbB2 and also other oncogenic kinases.
Methods
The student will learn various methods, including cell culture, DNA transfection, RNA interference, western blotting, co-immunoprecipitation, and confocal microscopy.
The work will be carried out in the Laboratory for Cellular and Molecular Cancer Research, Department of Pathology, Institute of Clinical Medicine, Rikshospitalet.
Link to the websites of the research group:
http://ous-research.no/huitfeldt/
http://www.med.uio.no/klinmed/english/research/groups/laboratory-molecular-cellular-cancer-research/index.html
How to down-regulate the oncoprotein ErbB2?
A number of human cancers are characterized by altered expression of receptors belonging to the epidermal growth factor receptor (EGFR) - or ErbB family of receptor tyrosine kinases, especially is overexpression of ErbB2/HER2 and/or ErbB3 associated with poor prognosis. To prevent uncontrolled cell growth, signaling from the ErbB family of receptors is controlled by endocytosis of the receptors. Therapeutic principles that cause endocytic down-regulation of the receptors and/or inhibit receptor activation and signaling are important in cancer treatment and a number of therapeutic anti-receptor antibodies, kinase inhibitors and other drugs are in clinical use or trials. ErbB2 is endocytosis resistant and the stabilization of ErbB2 is thought to depend on interaction with the chaperone Hsp90. Inhibition of Hsp90 causes down-regulation of ErbB2, and a number of Hsp90 inhibitors are in clinical trials. But since Hsp90 has hundreds of clients, its inhibition can have severe side-effects. Specificity of Hsp90 interactions is regulated by co-chaperones. Cdc37 acts as co-chaperone in the interaction between Hsp90 and clients containing kinase domains, and it has been shown that down-regulation of Cdc37 or destabilization of the Cdc37-Hsp90 complex induces down-regulation of ErbB2.