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K6PC-5, a direct activator of sphingosine kinase 1, promotes epidermal differentiation through intracellular Ca2+ signaling

Authors
 Jeong Hee Hong  ;  Jong-Kyung Youm  ;  Mi Jung Kwon  ;  Byeong Deog Park  ;  Yong-Moon Lee  ;  Syng-Ill Lee  ;  Dong Min Shin  ;  Seung Hun Lee 
Citation
 JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol.128(9) : 2166-2178, 2008 
Journal Title
 JOURNAL OF INVESTIGATIVE DERMATOLOGY 
ISSN
 0022-202X 
Issue Date
2008
MeSH
Amides/pharmacology* ; Animals ; Calcium/metabolism ; Calcium Signaling/drug effects ; Calcium Signaling/physiology* ; Cell Differentiation/drug effects* ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activators/pharmacology* ; Epidermis/drug effects ; Epidermis/metabolism* ; Epidermis/pathology ; Female ; Humans ; Hyperplasia ; Intermediate Filament Proteins/metabolism ; Keratin-5/metabolism ; Keratinocytes/drug effects ; Keratinocytes/metabolism ; Keratinocytes/pathology ; Lysophospholipids/metabolism* ; Membrane Proteins/metabolism ; Mice ; Mice, Hairless ; Mice, Inbred C57BL ; Neoplasms, Germ Cell and Embryonal/pathology ; Phosphotransferases (Alcohol Group Acceptor)/metabolism* ; Protein Precursors/metabolism ; Sphingosine/analogs & derivatives* ; Sphingosine/metabolism ; Teratocarcinoma/pathology
Keywords
Amides/pharmacology* ; Animals ; Calcium/metabolism ; Calcium Signaling/drug effects ; Calcium Signaling/physiology* ; Cell Differentiation/drug effects* ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activators/pharmacology* ; Epidermis/drug effects ; Epidermis/metabolism* ; Epidermis/pathology ; Female ; Humans ; Hyperplasia ; Intermediate Filament Proteins/metabolism ; Keratin-5/metabolism ; Keratinocytes/drug effects ; Keratinocytes/metabolism ; Keratinocytes/pathology ; Lysophospholipids/metabolism* ; Membrane Proteins/metabolism ; Mice ; Mice, Hairless ; Mice, Inbred C57BL ; Neoplasms, Germ Cell and Embryonal/pathology ; Phosphotransferases (Alcohol Group Acceptor)/metabolism* ; Protein Precursors/metabolism ; Sphingosine/analogs & derivatives* ; Sphingosine/metabolism ; Teratocarcinoma/pathology
Abstract
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, regulates multiple cellular responses such as Ca(2+) signaling, growth, survival, and differentiation. Because sphingosine kinase (SphK) is the enzyme directly responsible for production of S1P, many factors have been identified that regulate its activity and subsequent S1P levels. Here we synthesized a previously unidentified SphK activator, K6PC-5, and have studied its effects on intracellular Ca(2+) signaling in HaCaT cells and epidermal differentiation in murine skin. K6PC-5, a hydrophobic compound chemically named N-(1,3-dihydroxyisopropyl)-2-hexyl-3-oxo-decanamide, activated SphK (obtained from C57BL/6 murine blood and F9-12 cell lysates) in a dose-dependent manner. K6PC-5 induced both intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in HaCaT cells and Ca(2+) mobilization in hairless mouse epidermis. Both dimethylsphingosine (DMS) and dihydroxysphingosine (DHS), SphK inhibitors, and transfection of SphK1-siRNA blocked K6PC-5-induced increases in [Ca(2+)](i). The K6PC-5-induced [Ca(2+)](i) oscillations were dependent on thapsigargin-sensitive Ca(2+) stores and Ca(2+) entry, but independent of the classical phospholipase C-mediated pathway. In addition, K6PC-5 enhanced the expression of involucrin and filaggrin, specific differentiation-associated marker proteins in HaCaT cells, whereas transfection of SphK1-siRNA blocked the increase of involucrin. Topical K6PC-5 also enhanced the expression of involucrin, loricrin, filaggrin, and keratin 5 in intact murine epidermis. Finally, topical K6PC-5 inhibited epidermal hyperplasia by exerting antiproliferative effects on keratinocytes in murine epidermis. These results suggest that K6PC-5 acts to regulate both differentiation and proliferation of keratinocytes via [Ca(2+)](i) responses through S1P production. Thus, regulation of S1P levels may represent a novel approach for treatment of skin disorders characterized by abnormal differentiation and proliferation, such as atopic dermatitis and psoriasis.
Files in This Item:
T200800279.pdf Download
DOI
10.1038/jid.2008.66
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
Yonsei Authors
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Lee, Syng Ill(이승일)
Lee, Seung Hun(이승헌)
Hong, Jeong Hee(홍정희)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/106408
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