New insights into apoptotic signalling networks
Apoptosis, i.e. programmed cell death, is a precisely regulated process that leads to the elimination of surplus or damaged cells. The proteins of the Bcl-2 family play a key role in apoptosis. However, their complex interactions are not yet known in detail. A group of researchers from Germany, Austria and Switzerland is now trying to get to the bottom of this issue. Coordinated by the University of Konstanz, the researchers are jointly investigating the role of the Bcl-2 family signalling network during apoptosis. The insights obtained from the investigations may also have implications for the development of novel cancer therapeutics.
Every cell has a built-in “suicide programme” that governs its death and degradation. The process of programmed cell death, i.e. apoptosis, may for example be induced during embryogenesis in order to rearrange tissue structures or to remove defective cells. Disruption of apoptosis can lead to cancer. Whether or not a cell dies depends on a large number of pro- and anti-apoptotic signals that interact with each other, including proteins of the Bcl-2 family named after the family’s prototype, the protein B-cell lymphoma 2 (Bcl-2). The Bcl-2 family includes proteins that induce or inhibit apoptosis as well as so-called effector proteins that control the further course of apoptosis. With 15 known proteins, the human Bcl-2 family is a complex network of antagonistic signals that control the process of programmed cell death.
“Although some members of the Bcl-2 family have been known to be involved in apoptotic cell death since the 1970s and apoptosis research has made enormous progress over the past twenty years, answers to key questions related to the involvement of the Bcl-2 family in apoptotic cell death are still eluding researchers,” says Thomas Brunner, professor of biochemical pharmacology at the University of Konstanz. The enormous complexity of the apoptotic signalling pathways and the different interactions between Bcl-2 family members makes it difficult to decipher the way individual members function. While the function of the proteins is usually clearly defined under physiological conditions, it is still unclear how stress signals activate the Bcl-2 network. “A single work group can in principle only ever examine one aspect of the signalling network,” says Prof. Brunner, highlighting the difficulties faced by the researchers.
Combined expertise of an interdisciplinary group of researchers
Researchers from Germany, Austria and Switzerland have joined forces in order to answer unresolved questions on a number of different levels as well as increase scientific knowledge about the function of Bcl-2 proteins and their involvement in programmed cell death. The research consortium is coordinated by Prof. Brunner from the University of Konstanz and mainly involves scientists who have had previous contact with each other. “Many of the group leaders have known each other for a long time, some from the days of doctoral theses or postdoctoral research. They generally met up with one another on a regular basis and the idea of setting up a trinational research group eventually came up, which would specifically focus on apoptosis and the role of Bcl-2 in this process,” says Prof. Brunner.
In addition to apoptosis specialists, the scientists who initiated the project brought on board additional research groups with complementary expertise, for example in the field of bioinformatics, systems biology and biophysics. This led to the establishment of an expert team of researchers who are now working together on nine subprojects in order to address different aspects, topics, techniques and models and obtain a comprehensive picture and concept of apoptotic cell death and how individual Bcl-2 members interact with each other during apoptotic cell death. “The projects deal with fundamental as well as disease-related and even preclinical issues,” says Prof. Brunner referring to the broad range of topics addressed. The researchers are also working on experimental drugs, some of which are already undergoing clinical studies, in order to obtain information on the drugs’ molecular mechanisms.
One of the objectives is to develop a mathematical model based on already known data and results and use this model to calculate and predict potential interactions and dependencies of individual Bcl-2 family members. “Such mathematical model systems might also prove to be beneficial in the establishment and development of new therapeutic compounds,” explains Prof. Brunner relating to the Konstanz-based subproject, which also involves Prof. Tancred Frickey’s research group. “The members of our two research groups are carrying out joint experiments. We then integrate the resulting data into the mathematical network in order to model the high degree of complexity of the signals and better understand them,” continues Prof. Brunner.
The combination of compounds improves therapeutic effect
In addition to his role as coordinator of the trinational research group, Prof. Brunner’s own subproject is based on the observation that many tumour cells have developed resistances to certain cell death-inducing therapeutic compounds. This considerably limits the use of existing therapies for the treatment of cancer patients.
“Interestingly, the simultaneous application of two chemotherapeutic substances that have limited tumoricidal effects on their own can lead to the sensitisation of the tumour cell and hence more effective induction of apoptosis,” explains Brunner. The synergistic effect might be explained by the observation that apoptosis is induced by way of two independent signalling pathways, known as intrinsic and extrinsic pathways. The extrinsic pathway begins outside the cell through the activation of specific receptors on the cell surface. The intrinsic pathway is initiated from within the cell, i.e. the mitochondria, and involves proteins of the Bcl-2 family.
The co-administration of drugs that lead to the simultaneous activation of the intrinsic and extrinsic pathways increases the likelihood of a larger number of pro-apoptotic signals occurring, and leading to programmed cell death. While this effect is highly desirable in the treatment of tumours, in normal tissue cells it may lead to undesirable side effects and tissue damage. “Our project specifically focuses on the synergistic interactions of the intrinsic and extrinsic apoptotic pathways in tumour cells, but we are also addressing the potential effects on normal tissue cells,” explains Prof. Brunner. “We hope that the findings from our projects will in the long term enable the development of therapies that are currently unfeasible on the basis of the current state of knowledge,” concludes Brunner.
The international research group (FOR2036) “New insights into Bcl-2 family interactions: from biophysics to function” (New relations in the Bcl-2 family) involving researchers from Germany, Austria and Switzerland is a so-called “D-A-CH” (D – Germany, A – Austria, CH – Switzerland) collaboration that is funded by the respective national funding organisations for a period of three years. In addition to projects carried out by Prof. Brunner and Prof. Dr. Tancred Frickey (University of Konstanz), FOR2036 also includes projects run by Prof. Dr. Andreas Villunger (Biocenter Innsbruck Medical University), Prof. Dr. Thomas Kaufmann (University of Bern), Prof. Dr. Christoph Borner (University of Freiburg), Prof. Dr. Georg Häcker (vice coordinator, University of Freiburg), Dr. Ana J. Garcia-Saez (University of Tübingen), PD Dr. Alexander Egle (University Hospital Salzburg), PD Dr. Philipp Jost (Technical University Munich) and Dr. Miriam Erlacher (Freiburg University Medical Centre).
Prof. Dr. Thomas Brunner
Department of Biochemical Pharmacology
University of Konstanz