Inhibition of 12(S)‐lipoxygenase by geldanamycin, an inhibitor of heat shock protein 90, through repressing phosphorylation of Erk and JNK in the early phase and inducing Sp1 degradation in the late phase

Sp1 is a basic transcriptional factor that binds to the GC‐rich region in the promoter of target genes, and then activates their transcription. We previously reported that Sp1 interacts with heat shock protein 90£\(Hsp90£\) to recruit it to the promoter of 12(S)‐ lipoxygenase and regulates the transcription of 12(S)‐lipoxygenase by modulating DNA binding ability of Sp1, but the effect of Hsp90£\ on the expression of 12(S)‐lipoxygenase through Sp1 remains unclear. Previous studies also indicated that Sp1 phosphorylation affects DNA binding affinity and transcriptional activity of Sp1. In this study, we found that geldanamycin(GA, a specific inhibitor of Hsp90) could inhibit Sp1 phosphorylation and the transcriptional activity of 12(S)‐lipoxygenase gene. Moreover, when Hsp90£\ was inhibited by GA treatment in the early phase, the activities of Erk and JNK were repressed, resulting in the reduction of Sp1 phosphorylation. In our unpublished data, we also found that Sp1 could be phosphorylated at threonine 278/739 by JNK1 in mitotic stage to avoid degradation which is followed by ubiquitination. Furthermore, in this study, Sp1 dephosphorylation could induce Sp1 ubiquitination to cause Sp1 degradation at the late stage of GA treatment, but the mRNA of Sp1 could not be affected by GA. Taken together, our data indicate that Hsp90£\ affects the transcriptional activity of 12(S)‐ lipoxygenase by modulating Sp1 phosphorylation to regulate DNA binding affinity and stability of Sp1. Our future work is to continue studying whether Sp1 phosphorylation by Erk and JNK, which are affected by GA treatment, is important for the expression of 12(S)‐lipoxygenase.