Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation.
The proto-oncogene c-Jun plays an important role in regulating tumor progression. We previously reported that the serine/threonine phosphatase calcineurin (CaN, also called PP2B) dephosphorylates the C-terminus (Ser-243) of c-Jun, resulting in the increase in c-Jun and Sp1 interaction, and subsequent c-Jun-induced gene expression. Here, we demonstrate the interaction of c-Jun and CaN in the nucleus of living cells by fluorescence resonance energy transfer assay and that this interaction is mediated through the calmodulin-binding domain of CaN. Furthermore, c-Jun protein stability was altered by CaN-mediated dephosphorylation at the Ser-243 site of c-Jun. The half-life of the c-Jun mutant, c-Jun-S243A was longer than that of the wild-type c-Jun. Moreover, silencing of endogenous CaN expression led to increased c-Jun ubiquitination and decreased stability. In 46% of clinical cervical tissue samples obtained from patients with cervical cancer, enhanced c-Jun and CaN expression, as well as decreased phospho-Ser-243 expression levels were detected. Our results suggest that CaN stabilizes c-Jun by dephosphorylating c-Jun at Ser-243 to enhance its tumorigenic ability.
Huang
C-C
CC
Department of Pharmacology, College of Medicine, Tainan, Taiwan.
Wang
J-M
JM
Kikkawa
U
U
Mukai
H
H
Shen
M-R
MR
Morita
I
I
Chen
B-K
BK
Chang
W-C
WC
D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D002522:Chlorocebus aethiops; D006801:Humans; D009154:Mutation / Q000235:genetics; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D010768:Phosphoserine; D019703:Calcineurin