ß-arrestin 2 oligornerization controls the Mdm2-dependent inhibition of p53
ß-arrestin 2 oligornerization controls the Mdm2-dependent inhibition of p53
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DOI：
10.1073/pnas.0705550104
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发表时间：
2007-11-13
影响因子：
11.1
通讯作者：
Marullo, Stefano
中科院分区：
文献类型：
--
作者：
Boularan, Cedric;Scott, Mark G. H.;Marullo, Stefano
β-arrestins (beta-arrs) 是两种参与蛇形七螺旋受体调节和信号转导的普遍存在的蛋白质，形成由肌醇 1,2,3,4,5,6-六磷酸稳定的组成型同源和异源寡聚体 (1136)。据信单体 β-arr 在激动剂激活后与受体相互作用，因此，β-arr 寡聚物被认为代表静止的生物非活性状态。与此相反，我们在此报告，与原癌基因 Mdm2 的细胞核相互作用以及随后的滴定特别需要 β-arr2 寡聚物以及先前表征的 β-arr2 核细胞质穿梭。 IP6 结合位点的突变会损害寡聚化，减少与 Mdm2 的相互作用，并抑制 β-arr2 的 p53 依赖性抗增殖作用，而受体调节和信号传导的能力得以维持。这些观察结果表明，β-arr2 寡聚体的细胞内浓度可能控制细胞存活和增殖。
beta-arrestins (beta-arrs), two ubiquitous proteins involved in serpentine heptahelical receptor regulation and signaling, form constitutive homo- and heterooligomers stabilized by inositol 1,2,3,4,5,6-hexakisphosphate (1136). Monomeric beta-arrs are believed to interact with receptors after agonist activation, and therefore, beta-arr oligomers have been proposed to represent a resting biologically inactive state. In contrast to this, we report here that the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require beta-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of beta-arr2. Mutation of the IP6-binding sites impair oligomerization, reduce interaction with Mdm2, and inhibit p53-dependent antiproliferative effects of beta-arr2, whereas the competence for receptor regulation and signaling is maintained. These observations suggest that the intracellular concentration of beta-arr2 oligomers might control cell survival and proliferation.