Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation
Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation
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DOI：
10.1038/sj.onc.1210888
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发表时间：
2008-04-10
期刊：
影响因子：
8
通讯作者：
Chang, W-C
中科院分区：
文献类型：
--
作者：
Huang, C-C;Wang, J-M;Chang, W-C
原癌基因c-Jun在调节肿瘤进展中发挥着重要作用。我们之前报道过丝氨酸/苏氨酸磷酸酶钙调磷酸酶（CaN，也称为 PP2B）使 c-Jun 的 C 末端（Ser-243）去磷酸化，导致 c-Jun 和 Sp1 相互作用增加，以及随后 c-Jun 诱导的基因表达。在这里，我们通过荧光共振能量转移测定证明了活细胞核中 c-Jun 和 CaN 的相互作用，并且这种相互作用是通过 CaN 的钙调蛋白结合域介导的。此外，c-Jun 蛋白的稳定性因 CaN 介导的 c-Jun Ser-243 位点去磷酸化而改变。 c-Jun突变体c-Jun-S243A的半衰期比野生型c-Jun的半衰期长。此外，内源CaN表达的沉默导致c-Jun泛素化增加并降低稳定性。在从宫颈癌患者获得的 46% 的临床宫颈组织样本中，检测到 c-Jun 和 CaN 表达增强，以及磷酸-Ser-243 表达水平降低。我们的结果表明，CaN 通过使 c-Jun 在 Ser-243 处去磷酸化来稳定 c-Jun，从而增强其致瘤能力。
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.