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G Protein betagamma subunits augment UVB-induced apoptosis by stimulating the release of soluble heparin-binding epidermal growth factor from human keratinocytes

Cited 17 time in Web of Science Cited 19 time in Scopus
Authors
Seo, Miran; Lee, Mi-Jeong; Heo, Jin Hee; Lee, Yun-Il; Kim, Yeni; Kim, So-Young; Lee, Eun-So; Juhnn, Yong-Sung
Issue Date
2007-06-06
Publisher
American Society for Biochemistry and Molecular Biology
Citation
J Biol Chem. 282(34): 24720-24730
Keywords
*ApoptosisCell Line, TumorCulture Media, Conditioned/pharmacologyDose-Response Relationship, DrugEpidermal Growth Factor/*metabolismGTP-Binding Protein beta Subunits/chemistry/*physiologyGTP-Binding Protein gamma Subunits/chemistry/*physiologyHumansIntercellular Signaling Peptides and ProteinsKeratinocytes/*metabolism/pathologyModels, BiologicalPhosphorylationProtein BindingReceptor, Epidermal Growth Factor/metabolism*Ultraviolet Raysp38 Mitogen-Activated Protein Kinases/metabolismsrc-Family Kinases/metabolism
Abstract
UV radiation induces various cellular responses by regulating the activity of many UV-responsive enzymes, including MAPKs. The betagamma subunit of the heterotrimeric GTP-binding protein (Gbetagamma) was found to mediate UV-induced p38 activation via epidermal growth factor receptor (EGFR). However, it is not known how Gbetagamma mediates the UVB-induced activation of EGFR, and thus we undertook this study to elucidate the mechanism. Treatment of HaCaT-immortalized human keratinocytes with conditioned medium obtained from UVB-irradiated cells induced the phosphorylations of EGFR, p38, and ERK but not that of JNK. Blockade of heparin-binding EGF-like growth factor (HB-EGF) by neutralizing antibody or CRM197 toxin inhibited the UVB-induced activations of EGFR, p38, and ERK in normal human epidermal keratinocytes and in HaCaT cells. Treatment with HB-EGF also activated EGFR, p38, and ERK. UVB radiation stimulated the processing of pro-HB-EGF and increased the secretion of soluble HB-EGF in medium, which was quantified by immunoblotting and protein staining. In addition, treatment with CRM179 toxin blocked UV-induced apoptosis, but HB-EGF augmented this apoptosis. Moreover, UVB-induced apoptosis was reduced by inhibiting EGFR or p38. The overexpression of Gbeta(1)gamma(2) increased EGFR-activating activity and soluble HB-EGF content in conditioned medium, but the sequestration of Gbetagamma by the carboxyl terminus of G protein-coupled receptor kinase 2 (GRK2ct) produced the opposite effect. The activation of Src increased UVB-induced, Gbetagamma-mediated HB-EGF secretion, but the inhibition of Src blocked that. Overexpression of Gbetagamma increased UVB-induced apoptosis, and the overexpression of GRK2ct decreased this apoptosis. We conclude that Gbetagamma mediates UVB-induced human keratinocyte apoptosis by augmenting the ectodomain shedding of HB-EGF, which sequentially activates EGFR and p38.
ISSN
0021-9258 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17548351

http://hdl.handle.net/10371/68489
DOI
https://doi.org/10.1074/jbc.M702343200
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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