CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1 interactions.
CK1delta modulates the transcriptional activity of ERalpha via AIB1 in an estrogen-dependent manner and regulates ERalpha-AIB1 interactions.
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DOI：
10.1093/nar/gkp136
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发表时间：
2009-05
影响因子：
14.9
通讯作者：
Stebbing J
中科院分区：
文献类型：
--
作者：
Giamas G;Castellano L;Feng Q;Knippschild U;Jacob J;Thomas RS;Coombes RC;Smith CL;Jiao LR;Stebbing J
乳腺癌的发生通常需要核受体辅激活因子AIB 1/SRC-3的过度表达，其与雌激素受体-α（ERα）共同作用。ERα和AIB 1的磷酸化已被证明对其功能有深远的影响。此外，蛋白酶体介导的降解通过调节它们的稳定性和活性起主要作用。CK 1 δ是普遍存在的酪蛋白激酶-1家族的成员，与乳腺癌的进展有关。在这项研究中，我们发现ERα和AIB 1都是CK 1 δ的体外底物，并确定了一个新的CK 1 δ靶向的AIB 1磷酸化位点（S601），对AIB 1的共激活功能具有重要意义。CK 1 δ能够在体内与ERα和AIB 1相互作用，而乳腺癌细胞中CK 1 δ的过表达导致ERα与AIB 1的结合增加，这通过细胞裂解物的免疫共沉淀试验证实。使用基于siRNA的方法，荧光素酶报告基因测定和qRT-PCR，我们观察到CK 1 δ的沉默导致ERα转录活性降低，尽管ERα水平增加，类似于蛋白酶体抑制。我们提供的证据表明，AIB 1蛋白水平降低CK 1 δ沉默，在雌二醇依赖性的方式，这种不稳定性可以抑制预处理与蛋白酶体抑制剂MG 132。我们认为，ERα和AIB 1通过与CK 1 δ相互作用和磷酸化，特别是AIB 1的稳定性，影响ERα的转录活性，从而在乳腺癌的发展中发挥作用。
Oncogenesis in breast cancer often requires the overexpression of the nuclear receptor coactivator AIB1/SRC-3 acting in conjunction with estrogen receptor-α (ERα). Phosphorylation of both ERα and AIB1 has been shown to have profound effects on their functions. In addition, proteasome-mediated degradation plays a major role by regulating their stability and activity. CK1δ, a member of the ubiquitous casein kinase-1 family, is implicated in the progression of breast cancer. In this study, we show that both ERα and AIB1 are substrates for CK1δ in vitro, and identify a novel AIB1 phosphorylation site (S601) targeted by CK1δ, significant for the co-activator function of AIB1. CK1δ is able to interact with ERα and AIB1 in vivo, while overexpression of CK1δ in breast cancer cells results in an increased association of ERα with AIB1 as confirmed by co-immunoprecipitation assays from cell lysates. Using an siRNA-based approach, luciferase reporter assays and qRT-PCR, we observe that silencing of CK1δ leads to reduced ERα transcriptional activity, despite increased ERα levels, similarly to proteasome inhibition. We provide evidence that AIB1 protein levels are reduced by CK1δ silencing, in an estradiol-dependent manner; such destabilization can be inhibited by pre-treatment with the proteasome inhibitor MG132. We propose that differing activities adopted by ERα and AIB1 as a consequence of their interactions with and phosphorylation by CK1δ, particularly AIB1 stabilization, influence the transcriptional activity of ERα, and therefore have a role in breast cancer development.
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影响因子：
--
作者：
Alarid, ET;Bakopoulos, N;Solodin, N
通讯作者：
Solodin, N
影响因子：
--
作者：
Grisouard, Jean;Medunjanin, Senad;Mayer, Doris
通讯作者：
Mayer, Doris
影响因子：
9.8
作者：
Balaguer, P;François, F;Casellas, C
通讯作者：
Casellas, C
影响因子：
16
作者：
Lonard, DM;Nawaz, Z;O'Malley, BW
通讯作者：
O'Malley, BW
影响因子：
5.3
作者：
Amazit, Larbi;Pasini, Luigi;Mancini, Michael A.
通讯作者：
Mancini, Michael A.