The regulation of important signal molecules that are critical for the formation of various cell types can be influenced by a chemically produced variant of indirubin, a natural material used in traditional Chinese medicine. This was shown by scientists from Heidelberg University, Kaiserslautern and Jena. The researchers were also able to demonstrate for the first time that these signal molecules in the cell – regulatory SMAD proteins – are not only controlled through regulation of their activation but also through the available quantity of signal molecules in the non-activated state. Because cellular differentiation as well as tumour growth are tied to these processes, the studies suggest a new approach for both the preparation of induced pluripotent stem cells and the development of tumour treatments. The results of the research were published in the journal Chemistry & Biology.
Cellular differentiation decides which functions can be assumed and carried out by cells in the body. Their precise regulation has a decisive influence on embryonic development and later also plays an essential role in maintaining the activity of organs. After toxic damage, among other things, it is important that cells can react appropriately to limit damage and regenerate the tissue. This requires close communication between the cells, which is controlled by numerous signal molecules. "Only when all the parts of a signal path are present, cells can react to the signals from the environment with a coordinated programme. If one of these components is missing, the proper cellular response is inhibited", explains Prof. Dr. Stefan Wölfl from Heidelberg University's Institute of Pharmacy and Molecular Biotechnology.
How cellular differentiation is controlled during embryonic development and in the mature organism significantly depends on the family of TGFß/BMP growth factors. Representatives of these specific signal molecules also participate in the genesis and development of tumour diseases. Through their work, the researchers have demonstrated that the cells themselves influence how sensitively they react to growth factor signals. This occurs through the availability of the complementary signal mediators within the cell adapting to the given situation. The amount of available regulatory SMAD proteins (R-Smad proteins) in the cell is controlled on the level of synthesis, but in particular through the control of their degradation. This is performed by a special control system present in every cell. This ubiquitin proteasome system makes it possible for cellular proteins to be degraded in a controlled manner.
Earlier research already demonstrated that the degradation of activated R-Smad proteins occurs through the ubiquitin proteasome system, resulting in termination of the signals. "Our results now prove that the reservoir of non-activated R-SMAD signal mediators is also strictly controlled. This prevents corresponding external signals from activating an internal programme", says Prof. Wölfl. "For example, if growing tumour cells are dependent on this signal, these cells could be kept from surviving and cell death may even occur if the signal mediators could be deliberately removed." According to Prof. Wölfl, R-Smad proteins are also important mediators in cellular differentiation. "Reducing or removing these signal mediators from stem cells would cause them to no longer react to differentiation signals, so they would retain their stem cell properties as a result."
In their experiments, the researchers worked with a variant of the natural product indirubin that they chemically synthesised. The studies showed that the indirubin derivative led to a degradation of the R-Smad proteins in human cells. Thus, the signals transmitted by the TGFß/BMP growth factors are blocked. In this procedure, the indirubin variant intervenes in various processes that all contribute to depleting the concentration of R-Smad proteins in the cell. In particular, the activity of specific regulating enzymes called ubiquitin proteases is diminished, which protect proteins from degradation in the ubiquitin proteasome system.
The research was funded by the Federal Ministry of Education and Research (BMBF) within a joint research project focussed on medical system biology. The research team at the Institute of Pharmacy and Molecular Biotechnology of Heidelberg University collaborated with scientists from the University of Kaiserslautern and the Jena University Hospital as well as the Heidelberg University Hospital's Institute of Human Genetics.
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X. Cheng, H. Alborzinia, K.H. Merz, H. Steinbeisser, R. Mrowka, C. Scholl, I. Kitanovic, G. Eisenbrand, S. Wölfl: Indirubin Derivatives Modulate TGFβ/BMP Signaling at Different Levels and Trigger Ubiquitin-Mediated Depletion of Nonactivated R-Smads, Chemistry & Biology, Volume 19, Issue 11, 21 November 2012, Pages 1423-1436,