Gangoiti Patricia, Granado María H, Wang Shih Wei, Kong Jennifer Y, Steinbrecher Urs P, Gómez-Muñoz Antonio
Department of Biochemistry and Molecular Biology, University of the Basque Country, P.O. Box 644, 48080 Bilbao, Spain.
Cell Signal. 2008 Apr;20(4):726-36. doi: 10.1016/j.cellsig.2007.12.008. Epub 2007 Dec 17.
Ceramide 1-phosphate (C1P) was first shown to be mitogenic for fibroblasts, but the mechanisms whereby it stimulated cell proliferation have remained largely unknown. Here we demonstrate that C1P stimulates DNA synthesis and cell division in murine bone marrow-derived macrophages. C1P caused rapid phosphorylation of protein kinase B (PKB, also known as Akt), a downstream target of phosphatidylinositol 3-kinase (PI3-K). Selective inhibition of PI3-K blocked both DNA synthesis and cell growth. C1P induced phosphorylation of GSK-3beta, which is a major target of PKB, and this effect was also abolished by inhibition of PI3-K. In addition, C1P upregulated the expression of cyclin D1 and c-Myc, two major targets of GSK-3beta, which are important regulators of cell proliferation. C1P stimulated the activity of NF-kappaB, and inhibitors of this transcription factor completely blocked macrophage proliferation. Lastly, C1P induced phosphorylation of the mitogen activated protein kinases (MAPK) extracellularly regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK). Inhibition of ERK1/2 and JNK also blocked C1P-induced macrophage proliferation. It can be concluded that C1P stimulates macrophage proliferation through activation of the PI3-K/PKB, ERK and JNK pathways, and that GSK-3beta, c-Myc, cyclin D1, and NF-kappaB are important downstream effectors in this action.
神经酰胺 1 - 磷酸（C1P）最初被证明对成纤维细胞有促有丝分裂作用，但其刺激细胞增殖的机制在很大程度上仍不清楚。在此我们证明，C1P可刺激小鼠骨髓来源的巨噬细胞中的DNA合成和细胞分裂。C1P可导致蛋白激酶B（PKB，也称为Akt）快速磷酸化，PKB是磷脂酰肌醇3 - 激酶（PI3 - K）的下游靶点。选择性抑制PI3 - K可阻断DNA合成和细胞生长。C1P诱导糖原合成酶激酶3β（GSK - 3β）磷酸化，GSK - 3β是PKB的主要靶点，抑制PI3 - K也可消除这种作用。此外，C1P上调细胞周期蛋白D1和c - Myc的表达，这两个是GSK - 3β的主要靶点，是细胞增殖的重要调节因子。C1P刺激核因子κB（NF - κB）的活性，该转录因子的抑制剂可完全阻断巨噬细胞增殖。最后，C1P诱导丝裂原活化蛋白激酶（MAPK）细胞外调节激酶1和2（ERK1/2）以及c - Jun氨基末端激酶（JNK）磷酸化。抑制ERK1/2和JNK也可阻断C1P诱导的巨噬细胞增殖。可以得出结论，C1P通过激活PI3 - K/PKB、ERK和JNK途径刺激巨噬细胞增殖，并且GSK - 3β、c - Myc、细胞周期蛋白D1和NF - κB是这一作用中重要的下游效应分子。
