期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 90, 期 8, 页码 971-981出版社
SPRINGER
DOI: 10.1007/s00109-012-0865-4
关键词
c-Jun; Hypoxia inducible factor 1 alpha; JNK; Pseudolaric acid B; Ser63/73 phosphorylation
资金
- National Natural Science Foundation of China [81025020, 30730103, 81021062]
- National Basic Research Program of China [2012CB932502]
- National Science & Technology Major Project of China [2012ZX09301-001-002]
- State Key Laboratory of Biotherapy of China [SKLB200902]
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.
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