Pseudolaric acid B-driven phosphorylation of c-Jun impairs its role in stabilizing HIF-1alpha: a novel function-converter model

We have recently discovered that c-Jun executes a non-transcriptional function to stabilize hypoxia inducible factor 1 alpha (HIF-1 alpha) and that pseudolaric acid B (PAB) accelerates HIF-1 alpha degradation and phosphorylates c-Jun at Ser63/73. In this study, PAB was used as a probe to investigate whether and how the Ser63/73 phosphorylation of c-Jun regulates its functions. The PAB-induced reduction of HIF-1 alpha protein was rescued through supplying additional non-phosphorylated c-Jun. However, c-Jun siRNA, which reduced both the PAB-driven phosphorylated c-Jun and the total c-Jun protein, did not prevent the PAB-induced decrease in HIF-1 alpha. HIF-1 alpha was revealed to be co-immunoprecipitated only with the non-phosphorylated c-Jun. PAB increased the phosphorylated c-Jun while reducing the non-phosphorylated c-Jun at Ser63/73, which impaired its function in stabilizing HIF-1 alpha. Consequently, PAB led to the degradation of HIF-1 alpha, thus resulting in the decreased HIF-1 alpha-dependent expression of mdr-1 and VEGF. We accordingly propose a function-converter model of c-Jun: the Ser63/73 phosphorylation serves as a function converter to convert c-Jun from its non-transcriptional function to its transcriptional function.