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Sphingosine 1-phosphate induces EGFR expression via Akt/NF-kappaB and ERK/AP-1 pathways in rat vascular smooth muscle cells.
J Cell Biochem. 2008 Apr 15; 103(6):1732-46.JC

Abstract

Sphingosine 1-phosphate (S1P) has been shown to regulate expression of several genes in vascular smooth muscle cells (VSMCs) and contributes to arteriosclerosis. However, the mechanisms regulating epidermal growth factor receptor (EGFR) expression by S1P in aortic VSMCs remain unclear. Western blotting and RT-PCR analyses showed that S1P induced EGFR mRNA and protein expression in a time- and concentration-dependent manner, which was attenuated by inhibitors of MEK1/2 (U0126) and phosphatidylinositide 3-kinase (PI3K; wortmannin), and transfection with dominant negative mutants of ERK and Akt, respectively. These results suggested that S1P-induced EGFR expression was mediated through p42/p44 MAPK and PI3K/Akt pathways in VSMCs. In accordance with these findings, S1P stimulated phosphorylation of p42/p44 MAPK and Akt which was attenuated by U0126 and wortmannin, respectively. Furthermore, S1P-induced EGFR upregulation was blocked by a selective NF-kappaB inhibitor helenalin. Immunofluorescent staining and reporter gene assay revealed that S1P-induced activation of NF-kappaB was blocked by wortmannin, but not by U0126, suggesting that activation of NF-kappaB was mediated through PI3K/Akt. Moreover, S1P-induced EGFR expression was inhibited by an AP-1 inhibitor curcumin and tanshinone IIA. S1P-stimulated AP-1 subunits (c-Jun and c-Fos mRNA) expression was attenuated by U0126 and wortmannin, suggesting that MEK and PI3K/ERK cascade linking to AP-1 was involved in EGFR expression. Upregulation of EGFR by S1P may exert a phenotype modulation of VSMCs. This hypothesis was supported by pretreatment with AG1478 or transfection with shRNA of EGFR that attenuated EGF-stimulated proliferation of VSMCs pretreated with S1P, determined by XTT assay. These results demonstrated that in VSMCs, activation of Akt/NF-kappaB and ERK/AP-1 pathways independently regulated S1P-induced EGFR expression in VSMCs. Understanding the mechanisms involved in S1P-induced EGFR expression on VSMCs may provide potential therapeutic targets in the treatment of arteriosclerosis.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17902169

Citation

Hsieh, Hsi-Lung, et al. "Sphingosine 1-phosphate Induces EGFR Expression Via Akt/NF-kappaB and ERK/AP-1 Pathways in Rat Vascular Smooth Muscle Cells." Journal of Cellular Biochemistry, vol. 103, no. 6, 2008, pp. 1732-46.
Hsieh HL, Sun CC, Wu CB, et al. Sphingosine 1-phosphate induces EGFR expression via Akt/NF-kappaB and ERK/AP-1 pathways in rat vascular smooth muscle cells. J Cell Biochem. 2008;103(6):1732-46.
Hsieh, H. L., Sun, C. C., Wu, C. B., Wu, C. Y., Tung, W. H., Wang, H. H., & Yang, C. M. (2008). Sphingosine 1-phosphate induces EGFR expression via Akt/NF-kappaB and ERK/AP-1 pathways in rat vascular smooth muscle cells. Journal of Cellular Biochemistry, 103(6), 1732-46.
Hsieh HL, et al. Sphingosine 1-phosphate Induces EGFR Expression Via Akt/NF-kappaB and ERK/AP-1 Pathways in Rat Vascular Smooth Muscle Cells. J Cell Biochem. 2008 Apr 15;103(6):1732-46. PubMed PMID: 17902169.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosine 1-phosphate induces EGFR expression via Akt/NF-kappaB and ERK/AP-1 pathways in rat vascular smooth muscle cells. AU - Hsieh,Hsi-Lung, AU - Sun,Chi-Chin, AU - Wu,Chou-Bing, AU - Wu,Cheng-Ying, AU - Tung,Wei-Hsuan, AU - Wang,Hui-Hsin, AU - Yang,Chuen-Mao, PY - 2007/9/29/pubmed PY - 2008/8/30/medline PY - 2007/9/29/entrez SP - 1732 EP - 46 JF - Journal of cellular biochemistry JO - J. Cell. Biochem. VL - 103 IS - 6 N2 - Sphingosine 1-phosphate (S1P) has been shown to regulate expression of several genes in vascular smooth muscle cells (VSMCs) and contributes to arteriosclerosis. However, the mechanisms regulating epidermal growth factor receptor (EGFR) expression by S1P in aortic VSMCs remain unclear. Western blotting and RT-PCR analyses showed that S1P induced EGFR mRNA and protein expression in a time- and concentration-dependent manner, which was attenuated by inhibitors of MEK1/2 (U0126) and phosphatidylinositide 3-kinase (PI3K; wortmannin), and transfection with dominant negative mutants of ERK and Akt, respectively. These results suggested that S1P-induced EGFR expression was mediated through p42/p44 MAPK and PI3K/Akt pathways in VSMCs. In accordance with these findings, S1P stimulated phosphorylation of p42/p44 MAPK and Akt which was attenuated by U0126 and wortmannin, respectively. Furthermore, S1P-induced EGFR upregulation was blocked by a selective NF-kappaB inhibitor helenalin. Immunofluorescent staining and reporter gene assay revealed that S1P-induced activation of NF-kappaB was blocked by wortmannin, but not by U0126, suggesting that activation of NF-kappaB was mediated through PI3K/Akt. Moreover, S1P-induced EGFR expression was inhibited by an AP-1 inhibitor curcumin and tanshinone IIA. S1P-stimulated AP-1 subunits (c-Jun and c-Fos mRNA) expression was attenuated by U0126 and wortmannin, suggesting that MEK and PI3K/ERK cascade linking to AP-1 was involved in EGFR expression. Upregulation of EGFR by S1P may exert a phenotype modulation of VSMCs. This hypothesis was supported by pretreatment with AG1478 or transfection with shRNA of EGFR that attenuated EGF-stimulated proliferation of VSMCs pretreated with S1P, determined by XTT assay. These results demonstrated that in VSMCs, activation of Akt/NF-kappaB and ERK/AP-1 pathways independently regulated S1P-induced EGFR expression in VSMCs. Understanding the mechanisms involved in S1P-induced EGFR expression on VSMCs may provide potential therapeutic targets in the treatment of arteriosclerosis. SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/17902169/Sphingosine_1_phosphate_induces_EGFR_expression_via_Akt/NF_kappaB_and_ERK/AP_1_pathways_in_rat_vascular_smooth_muscle_cells_ L2 - https://doi.org/10.1002/jcb.21563 DB - PRIME DP - Unbound Medicine ER -