Protein researchers at the Ruhr University on the team from Junior Professors Dr. Clemens Steegborn and Dr. Dirk Wolters have clarified a complex safety mechanism that drives damaged cells to cell death when they can no longer be rescued. They identified on the one hand the part of Protein p66Shc that is responsible for a cell's suicide and they additionally ascertained the precise mechanism of its regulation.
In order for the self-destruction to be initiated, several protein components must work together as a complex. The complex can apparently be decomposed by the cell's repair mechanisms for precisely as long as the cell damages are reparable. Only when the cell is defective beyond repair does it perish. The researchers report on their work in the current issue of Proceedings of the National Academy of Sciences (PNAS).
Programmed Cell Death Provides Protection from Malfunctions and Diseases
The function and fate of a cell and subsequently also the functionality and lifespan of a complete organism are controlled by a complex network of signal proteins. Damages and malfunctions in this network are the cause of the aging process and a broad range of diseases which often occur more frequently with increasing age. One important protective mechanism against such malfunctions is programmed cell death, also known as apoptosis, by means of which heavily damaged cells decompose by themselves when their correct function is no longer assured.
Contributes to Arteriosclerosis and Age-Related Diabetes
Signal protein p66Shc functions as a molecular guardian and activates apoptosis as a solution to heavy cellular stress such as UV damage or toxic chemicals. "Mice in which the gene for p66Shc, which is closely related to the human equivalent, has been removed do in fact live some 30 % longer than normal mice, but the suspicion is that this gain in lifespan is achieved at the expense of correct function; i.e., that the organism is more susceptible to malfunctions due to cell damage", explains Dr. Steegborn. P66Shc plays a role in numerous aging-related diseases, for example arteriosclerosis or age-related diabetes. This makes the protein an interesting object for research, both in terms of the aging process and as a possible source of new medications. Despite its significance, the molecular mechanisms of p66Shc-induced apoptosis had nevertheless previously been insufficiently described.
Suicide Protein Under Strict Control
In their study, the Bochum-based researchers were initially able to identify the part of the p66Shc protein responsible for the apoptotic activity. It is a protein domain that produces hydrogen peroxide, a cell toxin, when amended with copper. "It is obvious that this toxic function of p66Shc must be subject to strict control", according to Dr. Steegborn. This is why for example the protein, after its activation, is transported into the mitochondria, the cell's power station, where it then initiates apoptosis.
Protective Mechanisms Can Break Down Stress and the Apoptosis Complex
The protein researchers were also able to explain an additional regulation mechanism: Activated by cellular stress, four p66Shc molecules form a stabile complex via Cystein-Cystein interactions . Only this complex can introduce the controlled cell death by causing the mitochondria to burst. The p66Shc activity can be arrested by the Glutathione and Thioredoxin cellular protective systems, which are capable of breaking down stress damages, substances that cause stress and the activated p66Shc complex. "p66Shc acts in this capacity as a stress sensor", explains Dr. Steegborn. "The cell's suicide program is apparently only started when these protective systems can no longer handle the cellular stress, and are subsequently also no long capable of deactivating p66Shc that has already been activated." These findings on the functionality and molecular regulation of p66Shc improve the understanding of the aging and disease process, and might in the future enable new approaches for intervention with effective agents.
Melanie Gertz; Frank Fischer; Dirk Wolters; Clemens Steegborn: Activation of the lifespan regulator p66Shc through reversible disulfide bond formation. In: PNAS, April 15, 2008 vol. 105, no. 15, 5705-5709
Junior Professor Dr. Clemens Steegborn, Institut für Physiologische Chemie, Medizinische Fakultät der Ruhr-Universität Bochum, 44780 Bochum, Germany Tel. +49-(0)234/32-27041, E-Mail: Clemens.Steegborn@rub.de
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