EphA2 Is an Essential Mediator of UV Radiation–Induced Apoptosis

Abstract

One of the physiologic consequences of excessive UV radiation (UVR) exposure is apoptosis. This critical response serves to eliminate genetically injured cells and arises, in part, from activation of DNA damage and p53 signaling. Other contributory pathways, however, likely exist but have not been fully characterized. In a recent global screen of UVR response genes in melanocytes, we identified the receptor tyrosine kinase EPHA2. Using a combination of genetic and pharmacologic approaches, we set out to investigate the upstream regulation of EphA2 by UVR and the functional consequences of this effect. We found that the UVR-associated increase in EphA2 occurs in melanocytes, keratinocytes, and fibroblasts from both human and murine sources. More specifically, UVR effectively up-regulated EphA2 individually in p53-null, p63-null, and p73-null murine embryonic fibroblasts (MEF), suggesting that the p53 family of transcription factors is not essential for the observed effect. However, inhibition of mitogen-activated protein kinase (MAPK) signaling by U0126 and PD98059 significantly reduced the UVR response whereas overexpression of oncogenic NRAS led to an increase in EphA2. These results confirm that UVR induces EphA2 by a p53-independent, but MAPK-dependent, mechanism. In response to UV irradiation, Epha2

Eph receptor and ephrin function in breast, gut, and skin epithelia

“…126 Accordingly, inflammatory signals and environmental stress impact epidermal EphA2 expression as this receptor is upregulated in keratinocytes by several pro-inflammatory cytokines and ultraviolet radiation. 123,[127][128][129] Interestingly, a cluster of ephrin-A genes (EFNA1, EFNA3, EFNA4) exists on the q arm of chromosome 1 in an area proximal to the epidermal differentiation complex harboring several genes coordinately regulated during keratinization. While ephrin-A1 is a known target of tumor necrosis factor a (TNFa) signaling in many cell types, including keratinocytes, very little is known about what regulates expression of most other ephrins in the epidermis.…”

“…In particular, EphA2 is upregulated in keratinocytes following UV radiation and was required for apoptosis. 129 Ephrin-A ligands appear to be particularly important for eliciting differentiation in keratinocytes, at least in cell culture models. In particular, delivery of soluble ephrin-A ligand led to keratinocyte stratification and differentiation.…”

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence

“…The prominent cellular response for wild-type MEFs after exposure to UV radiation is to undergo apoptosis and p53 plays an essential role in mediating this death pathway. 25,34 The p53 P/P mutation renders the cells resistant to p53-dependent apoptosis, 26,35 so to determine the extent of apoptosis in wild-type and mutant MEFs after UVB radiation in our system, we stained treatment. These results demonstrated that the mutant p53 is unable to downregulate prosurvival protein Bcl-2 in response to UVB exposure, which is essential for the induction of apoptosis.…”

Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics

“…EPHA2 has been reported to play a role in angiogenesis and tumor neovascularization as well as being a positive mediator of UV-induced and largely p53-independent apoptosis, but it can also affect oncogenesis in melanocytes. 65,66 Other genes, such as PML, 67 INPP5D 68 and APC2 69 are thought to be tumor suppressor genes. Cadherins are usually downregulated in tumors, 64 whereas IGF2 is often overexpressed in many types of cancers and thought to be an oncogene.…”