Anisomycin Selectively Desensitizes Signalling Components Involved in Stress Kinase Activation and fos and jun Induction

Abstract

Anisomycin, a translational inhibitor secreted by Streptomyces spp., strongly activates the stress-activated mitogen-activated protein (MAP) kinases JNK/SAPK (c-Jun NH 2 -terminal kinase/stress-activated protein kinase) and p38/RK in mammalian cells, resulting in rapid induction of immediate-early (IE) genes in the nucleus. Here, we have characterized this response further with respect to homologous and heterologous desensitization of IE gene induction and stress kinase activation. We show that anisomycin acts exactly like a signalling agonist in eliciting highly specific and virtually complete homologous desensitization. Anisomycin desensitization of a panel of IE genes (c-fos, fosB, c-jun, junB, and junD), using epidermal growth factor (EGF), basic fibroblast growth factor, (bFGF), tumor necrosis factor alpha (TNF-␣), anisomycin, tetradecanoyl phorbol acetate (TPA), and UV radiation as secondary stimuli, was found to be extremely specific both with respect to the secondary stimuli and at the level of individual genes. Further, we show that anisomycin-induced homologous desensitization is caused by the fact that anisomycin no longer activates the JNK/SAPK and p38/RK MAP kinase cascades in desensitized cells. In anisomycin-desensitized cells, activation of JNK/SAPKs by UV radiation and hyperosmolarity is almost completely lost, and that of the p38/RK cascade is reduced to about 50% of the normal response. However, all other stimuli produced normal or augmented activation of these two kinase cascades in anisomycin-desensitized cells. These data show that anisomycin behaves like a true signalling agonist and suggest that the anisomycin-desensitized signalling component(s) is not involved in JNK/SAPK or p38/RK activation by EGF, bFGF, TNF-␣, or TPA but may play a significant role in UV-and hyperosmolarity-stimulated responses.

The translation inhibitor anisomycin induces Elk-1-mediated transcriptional activation of egr-1 through multiple mitogen-activated protein kinase pathways

“…Our data conflict with previous reports that ANX activates JNK and p38 MAPK, but does not activate ERK cascades (Hazzalin et al, 1998). In other studies, however, ANX-induced activation of the ERK1/2 signaling pathway was observed in MCAS cells (Konishi et al, 2004).…”

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

“…41 These distinct functions of c-Jun might be determined by the interplay with additional factors such as the interaction with other AP-1 members. Similar to c-Jun, other AP-1 members can also be induced by DNA-damaging signals, 42,43 indicating their potential involvement in promoting apoptosis with c-Jun. The data presented here show that c-Jun, JunB and FosB are activated by chemotherapeutic drugs to regulate DNp73 degradation.…”

Behavioral impairments caused by injections of the protein synthesis inhibitor anisomycin after contextual retrieval reverse with time

“…Similar effects on protein degradation may occur when particularly high doses of anisomycin are delivered locally into specific brain regions, such as the hippocampus or amygdala, because higher doses may take longer to be eliminated from the brain. Additionally, anisomycin is known to have effects on mitogen-activated protein kinase (33) and catecholamines (34), so one needs to exercise caution when interpreting these results as implicating de novo protein synthesis.…”