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Controlled suicide

Our cells are programmed to be altruistic; even committing suicide for the benefit of the body as a whole. Professor Dr. Christoph Borner and his team at the University of Freiburg are investigating the molecular mechanisms of apoptosis, a process that helps to get rid of unnecessary or defective cells in an efficient way. The research of the Freiburg researchers also provides insights into the medical treatment of cells that do not want to die – cancer cells.

Embryos would not develop correctly without the controlled suicide of certain tissues and adult organisms would also deteriorate rapidly. In the brain of newborn babies, for example, precursors of neurons compete for contacts and only survive if they can establish proper contact with their synaptic partners. Controlled cell death establishes order. In adult organisms, apoptosis also removes cells that have been damaged by environmental influences such as UV radiation. And it also plays an important role in tissues that proliferate rapidly and frequently, for example skin, blood or the intestinal wall. Programmed cell death limits the life expectancy of cells and prevents natural mutations from accumulating in the genome over time. “That is why apoptosis has, in recent years, become increasingly important for cancer research,” said Professor Dr. Christoph Borner from the Institute of Molecular Medicine and Cell Research at the University of Freiburg. “Cancer cells can keep dividing because the cell death process fails.”

A promising protein family

The understanding of the molecular processes of apoptosis might enable scientists to induce apoptosis in tumours. However, apoptosis is a very complex process. In cells known as necrotic cells, the cell structure simply bursts when the cell is infected with a virus. Apoptotic cells, on the other hand, die a ‘clean’ death in that they shrink, become ball-shaped and then are fragmented. Certain structures on the membranes of the dying cells then attract immune system macrophages which take up the cell debris to prevent it from causing tissue inflammation.
A healthy cell (left) and an apoptotic cell (right).
A healthy cell (left) and an apoptotic cell (right). (Photo: Prof. Dr. Christoph Borner) © Prof. Dr. Christoph Borner
The molecules which induce and mediate apoptosis are protein-cleaving enzymes known as proteases. These molecules remove components of the cytoskeleton, something that contributes to the typical morphology of apoptotic cells. Borner’s team at the Institute of Molecular Medicine and Cell Research is investigating different proteases and has also shown that some of the proteases that are involved in apoptotic processes are normally used for the degradation of cellular proteins in times of energy deficiency – cathepsins. Another class of molecules involved in apoptosis is a protein family (currently 25 members) referred to as Bcl-2. The gene was discovered as the translocated locus in a B-cell leukaemia (hence the name). These molecules govern mitochondrial outer membrane permeabilisation and can be either pro-apoptotic or anti-apoptotic. Bcl-2 is an inhibitor of apoptosis; it prevents cellular suicide and ensures that the cells keep dividing.

Can the programme be manipulated?

Apoptotic cell bodies (red; already fragmented) being taken up by macrophages (green) of the immune system (Photo: Prof. Dr. Christoph Borner)
The Bcl-2 protein family also includes the two proteins Bax and Bak, which induce apoptosis. These two molecules make big holes in the membrane of mitochondria, cellular structures for the generation of energy. Cytochrome C and other proteins from the intermembrane space are then released into the mitochondria and activate apoptosis-mediating proteases. The permeabilisation of the mitochondria induces apoptosis. Bcl-2 and Bax/Bak are antagonists because Bcl-2 prevents Bax/Bak from making holes into the mitochondria. “This might be a potential target for anti-cancer drugs,” said Borner. “If we were able to find substances that revert the anti-apoptotic effect of Bcl-2, then we might be able to induce processes in the mitochondria that lead to the onset of apoptosis.

The Freiburg research team are currently investigating further BCl-2 family members that also activate apoptosis. These activators have a domain of approximately 25 amino acids which can reactivate the blocked Bax and Bak complex. “This is a very promising substance class and some pharmaceutical companies are already working hard to synthesise this short domain and use it as an anti-cancer drug in tumour cells,” said Borner. If they succeed, then the companies will have an effective drug to reprogramme cancer cells and force them to commit suicide. However, the substances are still in the testing phase and nobody knows about their potential side effects. Therefore, Borner and his colleagues are investigating whether the network of different Bcl-2 representatives interacts with other proteins. They are also interested in what exactly happens at the mitochondrial membrane and in the different ways that lead to programmed cell death. The better the mechanisms of controlled cell death are understood, the greater the chances of reprogramming them sometime in the future.

mn – 15 September 2008
© BIOPRO Baden-Württemberg GmbH
Further information:

Prof. Dr. Christoph Borner
Director of the Spemann Graduate School of Biology and Medicine (SGBM)
Institute of Molecular Medicine and Cell Research, ZBMZ
Stefan-Meier-Strasse 17
79104 Freiburg
Tel.: +49 (0)761/203-9618 (Büro); -9624 (Sekretariat); -9623 (Labor)
Fax: +49 (0)761/203-9620 (Büro); -9602 (Sekretariat)
E-mail: christoph.borner@uniklinik-freiburg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/controlled-suicide