title: Low dose ultraviolet B irradiation increases hyaluronan synthesis in epidermal keratinocytes via sequential induction of hyaluronan synthases Has1-3 mediated by p38 and Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling.
abstract: Hyaluronan, a major epidermal extracellular matrix component, responds strongly to different kinds of injuries. This also occurs by UV radiation, but the mechanisms involved are poorly understood. The effects of a single ultraviolet B (UVB) exposure on hyaluronan content and molecular mass, and expression of genes involved in hyaluronan metabolism were defined in monolayer and differentiated, organotypic three-dimensional cultures of rat epidermal keratinocytes. The signals regulating the response were characterized using specific inhibitors and Western blotting. In monolayer cultures, UVB increased hyaluronan synthase Has1 mRNA already 4 h postexposure, with a return to control level by 24 h. In contrast, Has2 and Has3 were persistently elevated from 8 h onward. Silencing of Has2 and especially Has3 decreased the UVB-induced accumulation of hyaluronan. p38 and Ca(2+)/calmodulin-dependent protein kinase II pathways were found to be involved in the UVB-induced up-regulation of Has2 and Has3 expression, respectively, and their inhibition reduced hyaluronan deposition. However, the expressions of the hyaluronan-degrading enzymes Hyal1 and Hyal2 and the hyaluronan receptor Cd44 were also up-regulated by UVB. In organotypic cultures, UVB treatment also resulted in increased expression of both Has and Hyal genes and shifted hyaluronan toward a smaller size range. Histochemical stainings indicated localized losses of hyaluronan in the epidermis. The data show that exposure of keratinocytes to acute, low dose UVB increases hyaluronan synthesis via up-regulation of Has2 and Has3. The simultaneously enhanced catabolism of hyaluronan demonstrates the complexity of the UVB-induced changes. Nevertheless, enhanced hyaluronan metabolism is an important part of the adaptation of keratinocytes to radiation injury.
authors: School of Medicine, Institute of Biomedicine/Anatomy, University of Eastern Finland, Kuopio Campus, Yliopistonranta 1 E, P.O. Box 1627, 70211 Kuopio, Finland. leena.rauhala@uef.fi
authors: Leena
authors: L
authors: Rauhala
authors: Lasse
authors: L
authors: Hämäläinen
authors: Pauliina
authors: P
authors: Salonen
authors: Geneviève
authors: G
authors: Bart
authors: Markku
authors: M
authors: Tammi
authors: Sanna
authors: S
authors: Pasonen-Seppänen
authors: Raija
authors: R
authors: Tammi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D004307:Dose-Response Relationship, Radiation; D004790:Enzyme Induction / Q000528:radiation effects; D015870:Gene Expression / Q000528:radiation effects; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D009281:Naphthalenes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010671:Phenylurea Compounds
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D014453:Glucuronosyltransferase; D018960:Hyaluronan Receptors; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid; D007527:Isoenzymes; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C491097:Has2 protein, rat; C491355:Has3 protein, rat; C452139:doramapimod; D010671:Phenylurea Compounds
keywords: CaMKII; Epidermis; Hyaluronan Synthase (HAS); Hyaluronate; Keratinocytes; UVB; p38
references: Cancer Res. 2010 Apr 1;70(7):2739-48
references: 20233865
references: Photochem Photobiol. 2011 Sep-Oct;87(5):1092-104
references: 21707633
references: Am J Pathol. 2000 Feb;156(2):529-36
references: 10666382
references: J Biol Chem. 2005 Apr 15;280(15):14636-44
references: 15722343
references: Cell Tissue Res. 2013 Jan;351(1):117-25
references: 23149717
references: J Biomed Mater Res A. 2003 Aug 1;66(2):317-29
references: 12889002
references: J Biol Chem. 2006 May 19;281(20):14026-40
references: 16565089
references: Prog Histochem Cytochem. 1994;29(2):1-81
references: 7892506
references: Am J Pathol. 2004 Oct;165(4):1331-41
references: 15466397
references: J Histochem Cytochem. 2008 Oct;56(10):901-10
references: 18574248
references: Int J Oncol. 2001 Nov;19(5):1057-61
references: 11605009
references: J Biol Chem. 2003 Dec 5;278(49):49495-504
references: 14506240
references: J Invest Dermatol. 1991 Jul;97(1):126-30
references: 2056182
references: J Biol Chem. 2010 Aug 20;285(34):26126-34
references: 20554532
references: Carcinogenesis. 1996 Sep;17(9):2073-6
references: 8824537
references: Am J Pathol. 2007 Nov;171(5):1451-61
references: 17982124
references: Photochem Photobiol. 2006 Sep-Oct;82(5):1342-7
references: 16724877
references: J Biol Chem. 2007 Dec 21;282(51):36777-81
references: 17981795
references: J Invest Dermatol. 1997 Aug;109(2):213-8
references: 9242510
references: J Biol Chem. 2006 Jun 9;281(23):15821-8
references: 16595683
references: J Invest Dermatol. 2006 Dec;126(12):2565-75
references: 17108903
references: Biochem Biophys Res Commun. 2006 Aug 18;347(1):83-8
references: 16808904
references: J Dermatol Sci. 2011 Aug;63(2):93-103
references: 21600739
references: Free Radic Biol Med. 1997;23(7):996-1001
references: 9358242
references: J Invest Dermatol. 2005 May;124(5):898-905
references: 15854028
references: J Biol Chem. 2003 Nov 21;278(47):47223-31
references: 12954638
references: Clin Dermatol. 2008 Mar-Apr;26(2):106-22
references: 18472055
references: J Biol Chem. 2003 Jun 20;278(25):22432-6
references: 12730222
references: Histochem Cell Biol. 2000 Apr;113(4):265-77
references: 10857478
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Development. 2009 Aug;136(16):2825-35
references: 19633173
references: Br J Dermatol. 2003 Jan;148(1):86-94
references: 12534600
references: Cancer Res. 2009 Jun 1;69(11):4648-55
references: 19458068
references: PLoS One. 2010 Apr 22;5(4):e10290
references: 20421975
references: J Invest Dermatol. 2008 Dec;128(12):2880-7
references: 18580964
references: J Invest Dermatol. 2003 Jun;120(6):1038-44
references: 12787132
references: J Invest Dermatol. 2008 Apr;128(4):797-807
references: 17943186
references: J Biol Chem. 2001 Jun 8;276(23):20428-35
references: 11262389
references: PLoS One. 2010 May 21;5(5):e10776
references: 20505830
references: J Biol Chem. 2011 May 20;286(20):18268-76
references: 21454612
references: Wound Repair Regen. 1999 Mar-Apr;7(2):79-89
references: 10231509
references: J Invest Dermatol. 2009 Aug;129(8):2046-58
references: 19225541
references: J Biol Chem. 2002 Feb 15;277(7):4589-92
references: 11717317
references: Birth Defects Res C Embryo Today. 2004 Mar;72(1):89-108
references: 15054906
references: Histochemistry. 1992 Sep;98(2):105-12
references: 1429018
references: Clin Exp Dermatol. 2010 Aug;35(6):650-7
references: 19886962
references: J Histochem Cytochem. 2011 Oct;59(10):908-17
references: 21832148
references: Exp Dermatol. 2010 Jul 1;19(7):654-60
references: 20456494
references: J Biol Chem. 2001 Sep 14;276(37):35111-22
references: 11451952
references: Arch Dermatol Res. 2011 May;303(4):277-84
references: 21448660
references: J Biol Chem. 2004 Mar 5;279(10):8753-60
references: 14676202
references: Connect Tissue Res. 2008;49(3):115-9
references: 18661324
references: J Invest Dermatol. 1999 May;112(5):751-6
references: 10233767
references: J Cell Biochem. 2009 Aug 1;107(5):873-80
references: 19415674
references: Cancer Res. 2002 Nov 15;62(22):6410-3
references: 12438225
references: Histochem Cell Biol. 2012 Jan;137(1):107-20
references: 22072421
references: Am J Pathol. 2006 Sep;169(3):823-30
references: 16936259
references: Mol Vis. 2009;15:577-83
references: 19325714
references: Eur J Pharm Sci. 2003 Sep;20(1):107-13
references: 13678799
references: J Biol Chem. 1999 Aug 27;274(35):25085-92
references: 10455188
references: Connect Tissue Res. 2008;49(3):215-8
references: 18661346
references: J Dermatol Sci. 1995 Sep;10(2):139-44
references: 8534612
references: Histochem Cell Biol. 2001 Oct;116(4):287-97
references: 11702187
references: J Biol Chem. 2005 Sep 9;280(36):31890-7
references: 16014622
references: Methods Enzymol. 1989;179:435-45
references: 2695771
references: J Biol Chem. 1998 Oct 30;273(44):28878-88
references: 9786890
references: Am J Physiol Gastrointest Liver Physiol. 2005 Sep;289(3):G462-70
references: 15677552
references: J Invest Dermatol. 1983 Feb;80(2):124-30
references: 6185597
references: Br J Dermatol. 2002 Apr;146 Suppl 61:1-6
references: 11966724
references: J Dermatol Sci. 2011 Oct;64(1):31-8
references: 21752603
references: PLoS One. 2012;7(7):e41340
references: 22848468
references: Int J Mol Med. 2006 Oct;18(4):713-9
references: 16964427
references: J Biol Chem. 2013 Feb 22;288(8):5973-83
references: 23303191
references: Exp Cell Res. 2004 Jun 10;296(2):123-34
references: 15149843
references: J Invest Dermatol. 2012 Jan;132(1):198-207
references: 21850020
references: Connect Tissue Res. 2001;42(3):187-95
references: 11913490
references: J Invest Dermatol. 1988 Mar;90(3):412-4
references: 2450149
references: Acta Physiol Scand. 1988 Nov;134(3):405-11
references: 3227957
references: Eur J Dermatol. 2000 Oct-Nov;10(7):505-10
references: 11056418
references: Photochem Photobiol Sci. 2009 Mar;8(3):299-308
references: 19255669
references: J Invest Dermatol. 2007 Mar;127(3):687-97
references: 17082783
references: Br J Dermatol. 2005 Oct;153(4):733-9
references: 16181453
references: FASEB J. 1997 Sep;11(11):843-9
references: 9285482
references: Arch Biochem Biophys. 2008 Mar 1;471(1):85-93
references: 18158910
references: J Biol Chem. 2007 Jun 1;282(22):16413-22
references: 17400550
references: J Investig Dermatol Symp Proc. 2009 Aug;14(1):50-2
references: 19675553
references: J Biol Chem. 2007 Jul 20;282(29):20999-1004
references: 17540771
references: Semin Cancer Biol. 2008 Aug;18(4):268-74
references: 18450474
references: Exp Cell Res. 2007 Aug 15;313(14):3005-15
references: 17512930