A Chemical Biology Approach to Understand the Rele.. (CB-HEDGEHOG)
A Chemical Biology Approach to Understand the Release of Sonic Hedgehog
Date du début: 1 mai 2014,
Date de fin: 30 avr. 2016
With 2,6 million new cases and 1,26 million deaths in 2012, cancer is the most important cause of death in the European Union (EU). The most common cancer forms are breast cancer, prostate cancer, bowel cancer and lung cancer. The Hedgehog pathway is one of the most important signalling pathways in tumourigenic processes and known to be involved in all of these four types of tumours that represent 52% of all cancer cases in the EU. Thereby, the key mediator of the signalling pathway in mammals is the protein Sonic Hedgehog (Shh). During its maturation, the morphogen Shh is post-translationally modified in the endoplasmic reticulum (e.g. autocatalytically cleaved and lipidated) and transported to the cell membrane. The subsequent release of the signalling fragment into the surrounding area of the expressing cell results in the formation of Shh multimers that are able to induce genes involved in the development of target cells. Due to its emerging impact on cancer development, several therapeutic approaches target the Shh pathway. Currently there are numerous ongoing clinical trials of corresponding drugs. In the context of the development of new cancer diagnostic and treatment approaches, it is of vital importance to fully understand the mechanisms of signalling pathways involved in the tumourigenic process in order to design effective therapies. However, crucial aspects of the Sonic Hedgehog pathway, particularly the mechanism of release of the Shh singalling complex from the expressing cell, remain to be elucidated, due to a lack of tools to investigate this multiply chemically modified protein complex. The aim of this project is to investigate the mechanism for release of Shh and the formation of well-defined active Shh multimers through a combination of organic synthesis with proteomics and cell biology to elucidate this essential process in molecular detail for the first time. This highly multidisciplinary approach lies at the cutting edge of chemical biology.
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