Impact of the p53 status of tumor cells on extrinsic and intrinsic apoptosis signaling

Franziska Wachter,Michaela Grunert,Irmela Jeremias,David M Weinstock,Cristina Blaj,Harald Ehrhardt

doi:10.1186/1478-811x-11-27

Abstract

BackgroundThe p53 protein is the best studied target in human cancer. For decades, p53 has been believed to act mainly as a tumor suppressor and by transcriptional regulation. Only recently, the complex and diverse function of p53 has attracted more attention. Using several molecular approaches, we studied the impact of different p53 variants on extrinsic and intrinsic apoptosis signaling.ResultsWe reproduced the previously published results within intrinsic apoptosis induction: while wild-type p53 promoted cell death, different p53 mutations reduced apoptosis sensitivity. The prediction of the impact of the p53 status on the extrinsic cell death induction was much more complex. The presence of p53 in tumor cell lines and primary xenograft tumor cells resulted in either augmented, unchanged or reduced cell death. The substitution of wild-type p53 by mutant p53 did not affect the extrinsic apoptosis inducing capacity.ConclusionsIn summary, we have identified a non-expected impact of p53 on extrinsic cell death induction. We suggest that the impact of the p53 status of tumor cells on extrinsic apoptosis signaling should be studied in detail especially in the context of therapeutic approaches that aim to restore p53 function to facilitate cell death via the extrinsic apoptosis pathway.

Highlights

The p53 protein is the best studied target in human cancer
We aimed to study the impact of the p53 status itself on extrinsic and intrinsic apoptosis sensitivity
The increased apoptosis sensitivity was not attributable to any regulation of apoptosis signaling proteins involved in TRAIL signaling

Summary

Introduction

The p53 protein is the best studied target in human cancer. For decades, p53 has been believed to act mainly as a tumor suppressor and by transcriptional regulation. We studied the impact of different p53 variants on extrinsic and intrinsic apoptosis signaling. The prediction of the precise action of p53 on a specific cell and within a special context remains the focus of research activities and the impact on transcriptional control and the cell cycle is strictly context-specific [2,3,4,5,6,7]. Targeted therapies that modulate a specific step of cell death induction in tumor cells represent one of the main goals of ongoing preclinical and clinical studies to improve cancer therapy. Within the research activities of the extrinsic cell death induction by death inducing ligands like TRAIL, the focus was exclusively drawn to the promising approaches of p53. We used different molecular approaches as has been done i.e. for tumorigenesis in different p53 genetic backgrounds before [14,15]

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