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.
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, doi: 10.1016/j.chembiol.2012.09.008
Prof. Dr. Stefan Wölfl
Institute of Pharmacy and Molecular Biotechnology
Phone: +49 (0)6221 54-4878, firstname.lastname@example.org
Communications and Marketing
Press Office, phone: +49 (0)6221 54-2311
Further Reports about: Biotechnology > cell death > cell type > cellular differentiation > cellular protein > embryonic development > human cell > Molecular Biotechnology > Molecular Target > proteins > signal molecule > Smad proteins > stem cells > synthetic biology > TGFß/BMP
More articles from Life Sciences:
Study details genes that control whether tumors adapt or die when faced with p53 activating drugs
23.05.2013 | University of Colorado Denver
Scientists announce Top 10 New Species
23.05.2013 | Arizona State University
New indicator molecules visualise the activation of auto-aggressive T cells in the body as never before
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to examine individual cells and their activity directly in the tissue.
The development of new microscopes and fluorescent dyes in ...
A fried breakfast food popular in Spain provided the inspiration for the development of doughnut-shaped droplets that may provide scientists with a new approach for studying fundamental issues in physics, mathematics and materials.
The doughnut-shaped droplets, a shape known as toroidal, are formed from two dissimilar liquids using a simple rotating stage and an injection needle. About a millimeter in overall size, the droplets are produced individually, their shapes maintained by a surrounding springy material made of polymers.
Droplets in this toroidal shape made ...
Frauhofer FEP will present a novel roll-to-roll manufacturing process for high-barriers and functional films for flexible displays at the SID DisplayWeek 2013 in Vancouver – the International showcase for the Display Industry.
Displays that are flexible and paper thin at the same time?! What might still seem like science fiction will be a major topic at the SID Display Week 2013 that currently takes place in Vancouver in Canada.
High manufacturing cost and a short lifetime are still a major obstacle on ...
University of Würzburg physicists have succeeded in creating a new type of laser.
Its operation principle is completely different from conventional devices, which opens up the possibility of a significantly reduced energy input requirement. The researchers report their work in the current issue of Nature.
It also emits light the waves of which are in phase with one another: the polariton laser, developed ...
Innsbruck physicists led by Rainer Blatt and Peter Zoller experimentally gained a deep insight into the nature of quantum mechanical phase transitions.
They are the first scientists that simulated the competition between two rival dynamical processes at a novel type of transition between two quantum mechanical orders. They have published the results of their work in the journal Nature Physics.
“When water boils, its molecules are released as vapor. We call this ...
23.05.2013 | Physics and Astronomy
23.05.2013 | Health and Medicine
23.05.2013 | Ecology, The Environment and Conservation
17.05.2013 | Event News
15.05.2013 | Event News
08.05.2013 | Event News