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Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis

Oncogene volume 20, pages 6503–6515 (2001)Cite this article

Abstract

The p53 tumor suppressor protein is mutated in more than 50% of all human cancers, which makes the study of its functions and activities critical for the understanding and management of cancer. In response to cellular stresses, p53 is activated and can mediate cell cycle arrest and/or apoptosis via the upregulation of numerous target genes. Here, we have identified EphA2 as a target gene of the p53 family, that is, p53, p73, and p63. We also found that an increase of EphA2 transcript levels correlated with an increase of EphA2 protein expression, and induction of EphA2 in response to DNA damage corresponded with p53 activation. Furthermore, we identified a p53 response element located within the EphA2 promoter that is responsive to wild-type p53, p73, and p63, but not mutant p53. Interestingly, the ligand for EphA2, ephrin-A1, is also regulated by p53. EphA2 and ephrin-A1 are members of the Eph family of receptor tyrosine kinases and ligands, which are implicated in a number of developmental processes. To analyse the role of EphA2 in p53-mediated tumor suppression, we generated stable cell lines capable of expressing exogenous EphA2 in a tetracycline-repressible system. We found that EphA2 expression resulted in an increase in apoptosis. Thus, we hypothesize that the activated EphA2 may serve to impair anti-apoptotic signaling, perhaps by disrupting focal adhesions and thereby sensitize cells to pro-apoptotic stimuli.

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Abbreviations

HA:

hemagglutinin

PBS:

phosphate buffered saline

kb:

kilobase

bp:

base pair

FACS:

fluorescence-activated cell sorting

HPV:

human papilloma virus

nt:

nucleotide

FAK:

focal adhesion kinase.

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Acknowledgements

We would like to thank Dr R Markowitz, S Nozell and A Willis for critical reading of this manuscript. We also thank Dr T Hunter for EphA2 cDNA (pNeoMSV-EphA2) and Dr B Wang for suggestions. This work is supported in part by Grants R29 CA76069 and RO1 CA81237 from the National Institutes of Health and Grant DAMD 17-97-1-7019 from the United States Department of Defense Breast Cancer Research Program.

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  1. Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, Georgia, USA

    Michael Dohn, Jieyuan Jiang & Xinbin Chen

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  1. Michael Dohn
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Correspondence to Xinbin Chen.

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Dohn, M., Jiang, J. & Chen, X. Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Oncogene 20, 6503–6515 (2001). https://doi.org/10.1038/sj.onc.1204816

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