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Formation of nuclear Bax/p53 complexes is associated with chemotherapy induced apoptosis

Oncogene volume 19, pages 6216–6228 (2000)Cite this article

Abstract

Mechanisms by which chemotherapeutic agents induce apoptosis are not completely understood. Current knowledge of the actual pharmacologic effects of chemotherapy and their biochemical mechanisms are better understood than the downstream events, which initiate the apoptotic cascade. The chemotherapeutic agent cisplatin causes DNA damage and can induce apoptosis in several types of human cancers. We found the formation of previously unreported nuclear complexes between the tumor suppressor protein p53 and the pro-apoptotic protein Bax, in human melanoma cell lines induced into apoptosis following cisplatin exposure. These detergent resistant complexes were detected: after wild type (wt) p53 and Bax increased in the nucleus; at the same time when active cytoplasmic apoptosis related protease, caspase 3/CPP32 appeared; and prior to the detection of apoptotic DNA fragmentation. Three channel fluorescence laser scanning confocal image microscopy revealed that the nuclear Bax/p53 complexes remained in the nucleus and localized proximal to DNA fragmentation sites as assayed by TUNEL after cisplatin exposure. Two human melanoma cell lines, expressing wt p53, were induced into apoptosis after cisplatin exposure, however they differed in the timing of this induction. In both cell lines the formation of nuclear Bax/p53 co-immunoprecipitable complexes correlated with the timing of the induction of apoptosis. The degree of apoptosis induced by different concentrations of cisplatin correlated with the amount of nuclear Bax/p53 complexes. The co-immunoprecipitation of Bax and p53 was found regardless of the antibodies tested and was specific since Bcl-xL/p53 complexes were not detected. Additionally, the human prostate cancer cell line, LNCaP, also formed nuclear Bax/p53 complexes only after apoptosis was induced by paclitaxel.

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Acknowledgements

Support for this work came from the Columbia Skin Disease Research Center grant NIH-NIAMS #P30AR 44535; the Dan Belsky Cancer Research Fund; Columbia Comprehensive Cancer Center Core Grant NCI-P30-CA13696-27 (RL Fine) and the 1999 AACR-Intergen Young Investigator Award (AJ Raffo). The authors would like to thank Drs Paul Brandt-Rauf, Ralph Buttyan and David Cobrinik for helpful discussions about the manuscript. The Confocal Microscope facility is part of the Herbert Irving Cancer Center of Columbia University under the direction of Dr Lisa Pon and supported in part by NIH grants #1S10 RR10506 and 5 P30 CA13696. The authors wish to thank Theresa Swayne, Facility Manager and Dr Pon for their help in obtaining the confocal images.

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  1. Division of Medical Oncology, Experimental Therapeutics Program, Columbia University, College of Physicians and Surgeons, 650 West 168th Street, Black Building, Room BB-20-25, New York, 10032, NY, USA

    Anthony J Raffo, Arianna L Kim & Robert L Fine

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Raffo, A., Kim, A. & Fine, R. Formation of nuclear Bax/p53 complexes is associated with chemotherapy induced apoptosis. Oncogene 19, 6216–6228 (2000). https://doi.org/10.1038/sj.onc.1203995

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