2008年3月
EphA2 is an essential mediator of UV radiation-induced apoptosis
CANCER RESEARCH
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- 巻
- 68
- 号
- 6
- 開始ページ
- 1691
- 終了ページ
- 1696
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1158/0008-5472.CAN-07-2372
- 出版者・発行元
- AMER ASSOC CANCER RESEARCH
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 AWAS led to an increase in EphA2. These results confirm that UVR induces EphA2 by a p53-independent, but MAPK-dependent, mechanism. In response to IN irradiation, Epha2(-/-) MEFs were highly resistant to UTR-mediated cytotoxicity and apoptosis whereas introduction of EphA2 into both wild-type and p53-null MEFs led to activation of an apoptotic program that can be blocked by caspase-8 inhibition. These functional findings suggest that EphA2 is in fact an essential p53-independent, caspase-8-dependent proapoptotic factor induced by UVR.
- リンク情報
- ID情報
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- DOI : 10.1158/0008-5472.CAN-07-2372
- ISSN : 0008-5472
- Web of Science ID : WOS:000254024400012