Original Article

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

Correspondence to: Kamal D. Mehta

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.—Dhawan, P., A. Bell, A. Kumar, C. Golden, and K. D. Mehta. 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. J. Lipid Res. 1999. 40: 1911;–1919.

Supplementary key words: anisomycin, hepatocyte growth factor, mitogen-activated protein kinase, LDL receptor induction

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