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

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.

• Authors: M Dohn, J Jiang, X Chen
• Journal: Oncogene (Oncogene) Vol. 20 Issue 45 Pg. 6503-15 (Oct 04 2001) ISSN: 0950-9232 [Print] England
• PMID: 11641774 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CKAP4 protein, human
• DNA-Binding Proteins
• Ephrin-A1
• Membrane Proteins
• Nuclear Proteins
• Phosphoproteins
• Proteins
• RNA, Neoplasm
• TP63 protein, human
• TP73 protein, human
• Trans-Activators
• Transcription Factors
• Tumor Protein p73
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Receptor Protein-Tyrosine Kinases
• Receptor, EphA2

Topics

• Apoptosis
• Cell Division
• DNA Damage
• DNA-Binding Proteins (physiology)
• Ephrin-A1
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Membrane Proteins
• Neoplasms (genetics, metabolism, pathology)
• Nuclear Proteins (physiology)
• Phosphoproteins (physiology)
• Phosphorylation
• Promoter Regions, Genetic
• Protein Biosynthesis
• Proteins (genetics)
• RNA, Neoplasm (biosynthesis)
• Receptor Protein-Tyrosine Kinases (genetics, metabolism, physiology)
• Receptor, EphA2
• Response Elements
• Trans-Activators (physiology)
• Transcription Factors
• Tumor Cells, Cultured
• Tumor Protein p73
• Tumor Suppressor Protein p53 (physiology)
• Tumor Suppressor Proteins
• Up-Regulation