ANISOMYCIN SELECTIVELY DESENSITIZES SIGNALING COMPONENTS INVOLVED IN STRESS KINASE ACTIVATION AND FOS AND JUN INDUCTION

Anisomycin, a translational inhibitor secreted bg Streptomyces spp,, s trongly activates the stress-activated mitogen-activated protein (MAP) kinases JNK/SAPK (c-Jun NH2-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 characterize d this response further with respect to homologous and heterologous de sensitization of IE gene induction and stress kinase activation. We sh ow that anisomycin acts exactly like a signalling agonist in eliciting highly specific and virtually complete homologous desensitization. An isomycin desensitization of a panel of IE genes (c-fos, fosB, c-jun, j unB, and junD), using epidermal growth factor (EGF), basic fibroblast growth factor, (bFGF), tumor necrosis factor alpha (TNF-alpha), anisom ycin, tetradecanoyl phorbol acetate (TPA), and UV radiation as seconda ry stimuli, was found to be extremely specific both with respect to th e secondary stimuli and at the level of individual genes, Further, we show that anisomycin-induced homologous desensitization is caused by t he fact that anisomycin no longer activates the JNK/SAPK and p38/RK MA P kinase cascades in desensitized eels. In anisomycin-desensitized cel ls, activation of JNK/SAPKs by UV radiation and hyperosmolarity is alm ost completely last, and that of the p38/RK cascade is reduced to abou t 50% of the normal response. However, all other stimuli produced norm al or augmented activation of these two kinase cascades in anisomycin- desensitized cells. These data show that anisomycin behaves like a tru e signalling agonist and suggest that the anisomycin-desensitized sign alling component(s) is not involved in JNK/SAPK or p38/RK activation b y EGF, bFGF, TNF-alpha, or TPA but may play a significant role in UV- and hyperosmolarity-stimulated responses.