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.