Gene defect causes chaos in the cell

Genetic defects interfere with signal processing and impair the immune system

Control cell © Medical University of Innsbruck
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Researchers at the Biozentrum Innsbruck and the Hannover Medical School, in collaboration with the University of Freiburg, have discovered a genetic cause for the disruption of signal transduction in cells. If due to a genetic defect, the cellular adapter p14 is not present in sufficient quantities, this leads to disorder in the cell. As a result, important players are no longer in the right place at the right time for the transmission of signals - resulting in a complex disorder of the immune system for affected patients.

The discovery is of great importance as cell cycle and differentiation disorders play a crucial role in many diseases, such as cancer, according to the researchers in Nature Medicine and The Journal of Cell Biology.

The cells of an organism continuously receive a variety of signals from their environment. Protein molecules on the cell surface record these signals and relay them to the inside of the cell, where they are recorded, interpreted and processed. Depending on the nature of the signal, the cells are stimulated to grow, differentiate, divide or die due to programmed cell death. If these complex processes derail, diseases such as cancer or immune disorders arise.

The scientists around Professor Lukas Huber from the Biocenter of the Medical University of Innsbruck are convinced that the spatial and temporal distribution of the actors involved in signal transmission are of crucial importance: "If this well-defined order within the cell is confused, then pathological changes occur" explains Huber. "We therefore want to learn how the signals in the cell are spatially and temporally distributed."

Genetic disorder

The importance of this new research direction became clear when the research group led by Professor Christoph Klein from the Hannover Medical School (MHH) became aware of a gene responsible for the cell adapter p14. The Department of Paediatrics, Pediatric Hematology and Oncology of MHH had identified a new immunodeficiency disorder characterized by growth and immune disorders as well as albinism. Smallest infections are enough to endanger the lives of the patients. display

In a long-term search for the genetic cause, they applied new methods of molecular biology and, in collaboration with Bodo Grimbacher from the University of Freiburg and the Helmholtz Center for Infection Research Braunschweig prove that the cell adapter p14 was only present in very small quantities. Due to this genetic defect, the white blood cells of the affected patients are reduced in their numbers and impaired in their function.

Long-term research perspective

As part of the special research area "Cell proliferation and cell death in tumors", Huber developed a new, innovative mouse model in Innsbruck over a period of four years. "This model allows us to specifically turn off certain genes in individual organs or cell types, " explains Huber. This enabled the researchers from Innsbruck to reproduce the results in the mouse that were observed in German patients.

"Clear proof, " says Huber, "is that the absence of the p14 adapter leads to a havoc in the cell, with the scent proteins placed in position on the adapter suddenly abolishing theirs As a result, signal propagation assisted by skeletal proteins is interrupted by kinases. " Thus, the scientists also provide a potential target for the therapy of this previously unknown disease.

Klein, a cancer specialist and expert in stem cell and gene therapy, sees not only opportunities in the development of targeted gene therapy for the affected patients, but also new starting points for new drugs in the treatment of cancer patients.

"The interdisciplinary international cooperation was decisive for this research success, " emphasize Klein and Huber, who expect many exciting results in their scientific cooperation in the future.

The data on the cell cycle and differentiation defect and the mouse model used were published by the scientists in December in the Journal of Cell Biology. The transference of this knowledge to the clinical significance for the immune system is now described in detail in the journal Nature Medicine.

(idw - Hannover Medical School / Biozentrum Innsbruck, 03.01.2007 - DLO)