Induction of ErbB2 by ultraviolet A irradiation: potential role in malignant transformation of keratinocytes.
Ultraviolet (UV) A (320-400 nm), which constitutes more than 90% of UV radiation in the sunlight that reaches the earth's surface, is considered a major cause of human skin photo-aging and skin cancer. Exposure of keratinocytes to UVA has previously been reported to lead to the activation of a variety of epidermal growth factor receptors (EGFR), including ErbB2, and ErbB2 activation is involved in skin tumor development. Here, we demonstrate that ErbB2 expression is enhanced by low-energy UVA (300-3000 mJ/cm(2)) irradiation in the skin tissues of both hairless mice and HaCaT keratinocytes. Luciferase reporter-gene activity using the 756-bp flanking region of the human erbB2 gene was increased by UVA irradiation. UVA irradiation also selectively increased the levels of activator protein (AP)-2 alpha, but not AP-2 beta and AP-2 gamma. The increase in the reporter gene activity of HaCaT cells exposed to UVA was abolished by mutation of the two AP-2 binding sites in the promoter region of the erbB2 gene. Inhibition of cAMP-dependent protein kinase caused complete blockage of ErbB2 induction and AP-2 alpha activation by UVA irradiation. Finally, we reveal that pre-exposure of HaCaT cells to UVA potentiates EGF-inducible anchorage-independent growth of the keratinocytes, which is significantly suppressed by ErbB2 inhibition. These results support the hypothesis that UVA enhances the expression of ErbB2 via cAMP- and protein kinase-dependent AP-2 alpha activation in keratinocytes, which may serve as a key mechanistic basis for the malignant transformation of keratinocytes exposed to UVA irradiation.
Han
Chang Yeob
CY
BK21 Project Team, Chosun University, Gwangju 501-759, South Korea.
Lim
Sung Chul
SC
Choi
Hong Seok
HS
Kang
Keon Wook
KW
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects*; D051379:Mice; D008812:Mice, Hairless; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D017868:Cyclic AMP-Dependent Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D050656:Transcription Factor AP-2; C508053:ERBB2 protein, human