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

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 alth ough exposure to anisomycin resulted in rapid and strong activation of p46/ 54(JNK) and p38(MAPK), with a delayed low level dual-phosphorylation of mit ogen/extracellular protein kinase (p42/44(MAPK)), low density lipoprotein ( LDL) receptor induction depends solely on the mild activation of p42/44MAPK Signaling cascade in HepC2 cells, Unlike hepatocyte growth factor (HGF) wh ich caused LDL receptor induction via rapid, strong, and Ras-dependent p42/ 44MAPK activation, anisomycin-induced p42/44MAPK activity and increased LDL receptor expression in a Ras-independent manner. Finally, we examined the role of the p42/44MAPK signaling cascade in LDL receptor induction by activ ating this kinase independently of anisomycin or HGF, By using estrogen-dep endent 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 c ascade with antiestrogen ICI 182,780 caused induction of LDL receptor expre ssion to the same level as observed with either HGF or anisomycin, Consiste nt with the role of p42/44(MAPK), induction was strongly inhibited by pretr eatment with the MEK-1/2 inhibitor PD98059.jlr Our observation that anisomy cin can use p42/44MAPK signaling cascade is a departure from established dr inking, and the results presented shows that activation of the p42/44MAPK a lone is sufficient to fully induce LDL receptor transcription., P., A. Bell , A. Kumar, C. Golden, and K. D. Mehta. Critical role of p42/44MAPK activat ion in anisomycin and hepatocyte growth factor-induced LDL receptor express ion: activation of Raf-1/MEK-l/p42/ 44MAPK cascade alone is sufficient to i nduce LDL receptor expression.