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Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo

Oncogene volume 20, pages 4601–4612 (2001)Cite this article

Abstract

The p53 tumor suppressor plays a key role in the cell's response to genotoxic stress and loss of this ‘guardian of the genome’ is an important step in carcinogenesis. The ability of p53 to induce apoptosis through transactivation of its target genes is critical for its function as tumor suppressor. We have found that overexpression of p53 in human cancer cell lines resulted in apoptosis as measured by PARP cleavage. Furthermore we observed cleavage of both caspase 9 and caspase 8 after overexpression of p53 and found that p53-dependent apoptosis was inhibited by either cellular (c-Flip-s, Bcl-XL) or pharmacological inhibitors of caspase 8 or caspase 9 respectively. These results indicate that p53 is mediating apoptosis through both the mitochondrial and death receptor pathways. To elucidate the relevant p53 target genes and examine the caspase pathways utilized in vivo, we treated p53+/+ and age matched p53−/− mice with 5 Gy ionizing radiation or 0.5 mg/animal dexamethasone and harvested tissues at 0, 6 and 24 h. We examined the mRNA expression of p21, bax, KILLER/DR5, FAS/APO1 and EI24/PIG8 using TaqMan real time quantitative RT–PCR in the spleen, thymus and small intestine. Although the basal mRNA levels of these genes did not depend on the presence of p53, we observed a p53-dependent induction of all these targets in response to γ-irradiation and a p53-independent regulation for p21 and KILLER/DR5 in response to dexamethasone. Furthermore, we have demonstrated that the relative induction of these p53 target genes is tissue specific. Despite observing otherwise similar levels of death in these tissues, our findings suggest that in some cases apoptosis mediated through p53 occurs by redundant pathways or by a ‘group effect’ while in other tissues one or few targets may play a key role in p53-dependent apoptosis. Surprisingly, KILLER/DR5 is the dominantly induced transcript in both the spleen and small intestine suggesting a potentially important role for this p53 target gene in vivo.

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Acknowledgements

This work was presented at the 91st Annual American Association for Cancer Research meeting in San Francisco, CA, USA on April 2nd, 2000, and at the 10th International p53 Workshop in Monterey, CA, USA on April 8th, 2000. The authors thank David T Dicker for excellent technical assistance with flow cytometry. We thank the MIT Biopolymers facility for hybridization of our Affymetix gene chips. TF Burns was supported in part by an NIH-MSTP training grant to the University of Pennsylvania. This work was supported by NIH grants CA 75454 (WS El-Deiry) and CA 75138 (EJ Bernhard and WS El-Deiry). WS El-Deiry is an Assistant Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Timothy F Burns & Wafik S El-Deiry

  2. Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Wafik S El-Deiry

  3. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Wafik S El-Deiry

  4. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Wafik S El-Deiry

  5. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Wafik S El-Deiry

  6. Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Eric J Bernhard

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Burns, T., Bernhard, E. & El-Deiry, W. Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo. Oncogene 20, 4601–4612 (2001). https://doi.org/10.1038/sj.onc.1204484

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