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DOI: 10.1055/s-0032-1330744
p53-regulierende Signaltransduktionskaskaden als Ziele für eine personalisierte Krebstherapie
p53-regulating Pathways as Targets for Personalized Cancer TherapyPublication History
Publication Date:
13 March 2013 (online)
![](https://www.thieme-connect.de/media/tumor/201302/lookinside/thumbnails/10.1055-s-0032-1330744-1.jpg)
Zusammenfassung
Der Tumorsuppressor p53 agiert nach Aktivierung durch verschiedene Upstream-Signalwege als Transkriptionsfaktor, der eine Vielzahl von Zielgenen aktiviert. Zwei wesentliche Gruppen von p53-Zielgenen können unterschieden werden. Solche, deren Funktion die Etablierung und Aufrechterhaltung von Zellzyklus-Checkpoints ist, und solche, die die Induktion des apoptotischen Zelltodes bewirken. Eine entscheidende Rolle in diesem zellulären Entscheidungsprozess spielt sicherlich der Schweregrad der genotoxischen Läsion. Die Art der zellulären Reaktion auf DNA. Schädigung ist als ein Kontinuum zu sehen, welches von einem Zellzyklusarrest bis hin zum apoptotischen Zelltod reicht und abhängig ist vom Schweregrad des Schadens. Welche molekularen Mechanismen die Entscheidung zwischen Zellzyklusarrest und Apoptose treffen, ist bisher weitestgehend unklar. Es ist dabei aus therapeutischer Sicht hochinteressant, diese Mechanismen aufzudecken, da die Induktion von p53-getriebener Apoptose in der Krebstherapie großen therapeutischen Nutzen birgt. Andererseits birgt die Induktion eines p53-abhängigen Zellzyklusarrests nach DNA-schädigender Chemotherapie die Gefahr von Resistenzbildungen, da die Tumorzellen durch den Zellzyklusarrest Zeit zur DNA-Reparatur gewinnen. In diesem Übersichtsartikel fassen wir die aktuellen Entwicklungen im Bezug auf p53-regulierende Mechanismen zusammen und geben einen Ausblick auf aktuell in Entwicklung und klinischer Testung befindliche therapeutische Ansätze zur Regulierung der p53-Antwort.
Abstract
The tumor suppressor p53 acts as a transcription factor downstream of many different stress-induced signaling pathways. Two major groups of p53-controlled genes can be distinguished. Those that mediate the initiation and maintenance of cell cycle checkpoints, and those driving apoptosis. An important determinant of the cellular reaction to DNA damage is the degree of genotoxic stress. The type of cellular response, which ranges from cell cycle arrest to apoptosis depends to a large extend on the severity of the genotoxic lesion. It remains largely unclear which molecular mechanisms govern the cellular decision between p53-driven cell cycle arrest and apoptosis. From a therapeutic perspective, this cellular decision is of utmost importance, as p53-driven apoptosis is therapeutically desired, when treating a malignant disease with DNA-damaging chemotherapy. However, a p53-driven cell cycle arrest might promote chemotherapy resistance, as it allows the tumor cells time to repair genotoxic lesions prior to the next cell division. Here, we summarize recent advances in our understanding of the molecular mechanisms controlling the functional outcome of p53 signaling. We further provide an outlook on the potential development of pharmacological interventions targeting the p53-regulating machinery to promote p53-driven apoptosis, while repressing p53-dependent cell cycle checkpoints.
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