Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes

J Invest Dermatol. 2008 Feb;128(2):389-97. doi: 10.1038/sj.jid.5701025. Epub 2007 Aug 23.

Abstract

Extracellular calcium (Ca2+(o)) potently induces the growth arrest and differentiation of human epidermal keratinocytes (HEKs). We report that Ca2+(o) markedly upregulates the human alkaline ceramidase 1 (haCER1) in HEKs; and its upregulation mediates the Ca2+(o)-induced growth arrest and differentiation of HEKs. haCER1 is the human ortholog of mouse alkaline ceramidase 1 that we previously identified. haCER1 catalyzed the hydrolysis of very long-chain ceramides to generate sphingosine (SPH). This in vitro activity required Ca2+. Ectopic expression of haCER1 in HEKs decreased the levels of D-e-C(24:1)-ceramide and D-e-C(24:0)-ceramide but elevated the levels of both SPH and its phosphate (S1P), whereas RNA interference-mediated knockdown of haCER1 caused the opposite effects on the levels of these sphingolipids in HEKs. Similar to haCER1 overexpression, Ca2+(o) increased the levels of SPH and S1P, and this was attenuated by haCER1 knockdown. haCER1 knockdown also inhibited the Ca2+(o)-induced growth arrest of HEKs and the Ca2+(o)-induced expression of keratin 1 and involucrin in HEKs. In addition, the acid ceramidase (AC) was also upregulated by Ca2+(o); and its knockdown attenuated the Ca2+(o)-induced expression of keratin 1 and involucrin in HEKs. These results strongly suggest that upregulation of haCER1 and AC mediates the Ca2+(o)-induced growth arrest and differentiation of HEKs by generating SPH and S1P.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acid Ceramidase
  • Alkaline Ceramidase
  • Amidohydrolases / genetics
  • Amidohydrolases / metabolism*
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Cell Differentiation / physiology
  • Cell Division / physiology
  • Cells, Cultured
  • Ceramidases
  • Ceramides / metabolism
  • Endoplasmic Reticulum / enzymology
  • Epidermal Cells
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • Fatty Acids, Unsaturated / metabolism
  • Galactosylgalactosylglucosylceramidase / genetics
  • Galactosylgalactosylglucosylceramidase / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / enzymology*
  • RNA, Small Interfering
  • Substrate Specificity
  • Up-Regulation / physiology

Substances

  • Ceramides
  • Fatty Acids, Unsaturated
  • RNA, Small Interfering
  • Epidermal Growth Factor
  • Galactosylgalactosylglucosylceramidase
  • Amidohydrolases
  • ACER1 protein, human
  • ACER2 protein, human
  • ASAH1 protein, human
  • Acer1 protein, mouse
  • Acid Ceramidase
  • Alkaline Ceramidase
  • Asah1 protein, mouse
  • Ceramidases
  • Calcium