Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes
Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes
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DOI：
10.1038/sj.jid.5701025
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发表时间：
2008-02-01
影响因子：
6.5
通讯作者：
Mao, Cungui
中科院分区：
文献类型：
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作者：
Sun, Wei;Xu, Ruijuan;Mao, Cungui
细胞外钙（Ca-o(2+)）能诱导人表皮角质形成细胞（HEKs）的生长停滞和分化。我们报道了Ca-o（2+）在HEKs中显著上调人碱性神经酰胺酶1 (haCER1)；它的上调介导了cao2_1诱导的HEKs生长停滞和分化。haCER1是我们之前发现的小鼠碱性神经酰胺酶1的人类同源物。haCER1催化超长链神经酰胺水解生成鞘氨醇（SPH）。这种体外活性需要Ca2+。haCER1在HEKs中的异位表达降低了d -e- c -24:1-神经酰胺和d -e- c -24:0-神经酰胺的水平，但升高了SPH及其磷酸盐（S1P）的水平，而RNA干扰介导的haCER1的下调对HEKs中这些鞘脂的水平产生了相反的影响。与haCER1过表达类似，Ca-o（2+）增加了SPH和S1P的水平，并通过敲低haCER1而减弱。haCER1敲低也抑制了Ca-o（2+）诱导的hek生长停滞和Ca-o（2+）诱导的hek中角蛋白1和天花素的表达。此外，Ca-o（2+）也上调了酸性神经酰胺酶（AC）；其敲低可减弱Ca-o（2+）诱导的HEKs中角蛋白1和天花素的表达。这些结果强烈表明，haCER1和AC的上调通过产生SPH和S1P介导Ca-o（2+）诱导的HEKs生长停滞和分化。
Extracellular calcium (Ca-o(2+)) potently induces the growth arrest and differentiation of human epidermal keratinocytes (HEKs). We report that Ca-o(2+) markedly upregulates the human alkaline ceramidase 1 (haCER1) in HEKs; and its upregulation mediates the Cao2_-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, Ca-o(2+) increased the levels of SPH and S1P, and this was attenuated by haCER1 knockdown. haCER1 knockdown also inhibited the Ca-o(2+)-induced growth arrest of HEKs and the Ca-o(2+)-induced expression of keratin 1 and involucrin in HEKs. In addition, the acid ceramidase (AC) was also upregulated by Ca-o(2+); and its knockdown attenuated the Ca-o(2+)-induced expression of keratin 1 and involucrin in HEKs. These results strongly suggest that upregulation of haCER1 and AC mediates the Ca-o(2+)-induced growth arrest and differentiation of HEKs by generating SPH and S1P.