title: Pseudolaric acid B-driven phosphorylation of c-Jun impairs its role in stabilizing HIF-1alpha: a novel function-converter model.
abstract: We have recently discovered that c-Jun executes a non-transcriptional function to stabilize hypoxia inducible factor 1α (HIF-1α) and that pseudolaric acid B (PAB) accelerates HIF-1α 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-1α 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-1α. HIF-1α 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-1α. Consequently, PAB led to the degradation of HIF-1α, thus resulting in the decreased HIF-1α-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.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.forename: Mei-Hong
authors.initials: MH
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ying-Qing
authors.initials: YQ
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Yang
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Yue
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
mesh_terms: D015153:Blotting, Western; D004224:Diterpenes / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D047468:Immunoprecipitation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004224:Diterpenes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016755:Proto-Oncogene Proteins c-jun; C058391:pseudolaric acid B