Gq protein mediates UVB-induced cyclooxygenase-2 expression by stimulating HB-EGF secretion from HaCaT human keratinocytes.
Ultraviolet (UV) radiation induces cyclooxygenase-2 expression to produce cellular responses including aging and carcinogenesis in skin. We hypothesised that heterotrimeric G proteins mediate UV-induced COX-2 expression by stimulating secretion of soluble HB-EGF (sHB-EGF). In this study, we aimed to elucidate the role and underlying mechanism of the alpha subunit of Gq protein (Galphaq) in UVB-induced HB-EGF secretion and COX-2 induction. We found that expression of constitutively active Galphaq (GalphaqQL) augmented UVB-induced HB-EGF secretion, which was abolished by knockdown of Galphaq with shRNA in HaCaT human keratinocytes. Galphaq was found to mediate the UVB-induced HB-EGF secretion by sequential activation of phospholipase C (PLC), protein kinase Cdelta (PKCdelta), and matrix metaloprotease-2 (MMP-2). Moreover, GalphaqQL mediated UVB-induced COX-2 expression in an HB-EGF-, EGFR-, and p38-dependent manner. From these results, we concluded that Galphaq mediates UV-induced COX-2 expression through activation of EGFR by HB-EGF, of which ectodomain shedding was stimulated through sequential activation of PLC, PKCdelta and MMP-2 in HaCaT cells.
Seo
MiRan
M
Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Republic of Korea.
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Yong-Sung
YS
D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000201:enzymology / Q000528:radiation effects*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D015595:Skin Aging; D012878:Skin Neoplasms / Q000201:enzymology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048051:p38 Mitogen-Activated Protein Kinases; D054801:Phosphoinositide Phospholipase C; D020778:Matrix Metalloproteinase 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11