Critical role of p42/44(MAPK) activation in anisomycin and hepatocyte growth factor-induced LDL receptor expression: Activation of Raf-1/MEK- 1/p42/44(MAPK) cascade alone is sufficient to induce LDL receptor expression

Punita Dhawan, April Bell, Amit Kumar, Carmen Golden, Kamal D. Mehta

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

The protein synthesis inhibitor anisomycin activates stress-related mitogen-activated protein kinases (MAPKs), namely, c-jun NH2-terminal kinase (p46/54(JNK)) and p38(MAPK) in mammalian cells. In this paper, we show that although exposure to anisomycin resulted in rapid and strong activation of p46/54(JNK) and p38(MAPK), with a delayed low level dual-phosphorylation of mitogen/extracellular protein kinase (p42/44(MAPK)), low density lipoprotein (LDL) receptor induction depends solely on the mild activation of p42/44(MAPK) signaling cascade in HepG2 cells. Unlike hepatocyte growth factor (HGF) which caused LDL receptor induction via rapid, strong, and Ras- dependent p42/44(MAPK) activation, anisomycin-induced p42/44(MAPK) activity and increased LDL receptor expression in a Ras-independent manner. Finally, we examined the role of the p42/44(MAPK) signaling cascade in LDL receptor induction by activating this kinase independently of anisomycin or HGF. By using estrogen-dependent human Raf-1 protein kinase in transient transfection assays, we show that the exclusive activation of the Raf-1/MEK-1/p42/44(MAPK) signaling cascade with antiestrogen ICI 182,780 caused induction of LDL receptor expression to the same level as observed with either HGF or anisomycin. Consistent with the role of p42/44(MAPK), induction was strongly inhibited by pretreatment with the MEK-1/2 inhibitor PD98059. Our observation that anisomycin can use p42/44(MAPK) signaling cascade is a departure from established thinking, and the results presented shows that activation of the p42/44(MAPK) alone is sufficient to fully induce LDL receptor transcription.

Original languageEnglish (US)
Pages (from-to)1911-1919
Number of pages9
JournalJournal of Lipid Research
Volume40
Issue number10
StatePublished - Oct 1999

Keywords

  • Anisomycin
  • Hepatocyte growth factor
  • LDL receptor induction
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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