Blockage of the ERK signaling pathway abrogates the SCAP ligand-induced transcriptional activation of the LDL receptor gene in HepG2 cells

  • Authors:
    • Parveen Abidi
    • Fang Zhang
    • Cong Li
    • Jingwen Liu
  • View Affiliations

  • Published online on: November 1, 2005     https://doi.org/10.3892/ijmm.16.5.779
  • Pages: 779-785
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Abstract

Previous studies identified the putative SCAP ligands including compound GW707 as a new class of up-regulators of LDL receptor (LDLR) transcription by activation of the sterol-regulatory element binding proteins (SREBP). These compounds increase LDLR expression in hepatoma cells in vitro and lower plasma LDL-c in hamsters. However, it is unknown, what signaling pathways are utilized by these agents that lead to the activation of LDLR transcription. Here, we report that the ERK signaling cascade is critically involved in GW707-mediated induction of LDLR expression. We show that: a) blocking ERK activation with U0126, the inhibitor of ERK upstream kinase MEK, completely abolishes the inducing effects of GW707 on LDLR promoter activity, LDLR mRNA expression, and DiI-LDL uptake in HepG2 cells; b) treating HepG2 cells with GW707 induces a dose-dependent conversion of SREBP-2 from the 125 kDa precursor form to the 68 kDa activated form and U0126 does not inhibit this cleavage process, but U0126 significantly reduces the total amount of SREBP-2 protein in GW707-treated cells without affecting the expression levels of other proteins involving in SREBP processing; and c) inhibition of ERK signaling pathway has no effects on the promoter activity or mRNA expression of SREBP-2. Collectively, these new findings establish an important role of ERK signaling pathway in SCAP ligand-induced transcription of LDLR and imply that the protein synthesis or turnover rate of SREBP-2 may be regulated by ERK.

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November 2005
Volume 16 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Abidi P, Zhang F, Li C and Liu J: Blockage of the ERK signaling pathway abrogates the SCAP ligand-induced transcriptional activation of the LDL receptor gene in HepG2 cells. Int J Mol Med 16: 779-785, 2005
APA
Abidi, P., Zhang, F., Li, C., & Liu, J. (2005). Blockage of the ERK signaling pathway abrogates the SCAP ligand-induced transcriptional activation of the LDL receptor gene in HepG2 cells. International Journal of Molecular Medicine, 16, 779-785. https://doi.org/10.3892/ijmm.16.5.779
MLA
Abidi, P., Zhang, F., Li, C., Liu, J."Blockage of the ERK signaling pathway abrogates the SCAP ligand-induced transcriptional activation of the LDL receptor gene in HepG2 cells". International Journal of Molecular Medicine 16.5 (2005): 779-785.
Chicago
Abidi, P., Zhang, F., Li, C., Liu, J."Blockage of the ERK signaling pathway abrogates the SCAP ligand-induced transcriptional activation of the LDL receptor gene in HepG2 cells". International Journal of Molecular Medicine 16, no. 5 (2005): 779-785. https://doi.org/10.3892/ijmm.16.5.779