Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation
Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation
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DOI：
10.1677/erc-06-0020
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发表时间：
2007-03-01
影响因子：
3.9
通讯作者：
Marino, Maria
中科院分区：
文献类型：
--
作者：
Galluzzo, Paola;Caiazza, Francesco;Marino, Maria
由17 β-雌二醇（E2）调节的细胞功能在激素与其受体结合后开始（即，ER α和ER β）。这些作为配体依赖性转录因子反式激活靶基因。此外，E2诱导非基因组作用，其激活由位于质膜的一部分ER触发。棕榈酰化允许ER α定位于质膜，与小窝蛋白-1缔合，并且在E2刺激时，激活与细胞增殖相关的快速信号。存在一种机制，允许ER β定位在质膜上，其在抗增殖E2效应中的假定作用是完全未知的。在此，ER β经历棕榈酰化的易感性和该过程所起的作用已经在含有内源性ER β的DLD-1中或在用ER β或ER α表达载体瞬时转染的HeLa细胞中进行了分析。至于ER α，棕榈酰化对于ER β在质膜上的定位及其与小窝蛋白-11的缔合是必需的，但是与ER α相反，E2结合增加了ER β与小窝蛋白-11和MAPK家族的p38成员的缔合。此外，棕榈酰酰基转移酶（PAT）抑制剂阻断ER β-E2复合物激活p38的能力，从而损害下游促凋亡级联的受体依赖性激活（即，半胱天冬酶-3活化和聚（ADP-核糖）聚合酶（PARP）裂解）。因此，棕榈酰化必须被认为是ER β的分子装置，其允许这些受体与质膜相互作用并调节E2诱导的与该激素的抗增殖作用相关的非基因组功能。
The cellular functions regulated by 17 beta-estradiol (E2) start after the hormone binds to its receptors (i.e., ER alpha and ER beta). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERa to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ER beta localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ER beta to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ER beta or in HeLa cells transiently transfected with ER beta or ERa expression vectors. As for ERa, palmitoylation is necessary for ER beta localization at the plasma membrane and its association with caveolin-11 but, in contrast to ER alpha, the E2 binding increases ER beta association with caveolin-11 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ER beta-E2 complex to activate p38 impairing the receptor-dependent activation of downstream pro-apoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ER beta, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the anti-proliferative effect of this hormone.