癌蛋白 Bcl-3 可以通过从选定的 kappa B 位点去除抑制性 p50 同源二聚体来促进 NF-kappa B 介导的反式激活。,The EMBO Journal

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癌蛋白 Bcl-3 可以通过从选定的 kappa B 位点去除抑制性 p50 同源二聚体来促进 NF-kappa B 介导的反式激活。
The EMBO Journal ( IF 9.4 ) Pub Date : 1993-10-01 , DOI: 10.1002/j.1460-2075.1993.tb06067.x
G Franzoso ₁ , V Bours , V Azarenko , S Park , M Tomita-Yamaguchi , T Kanno , K Brown , U Siebenlist

Affiliation

以前，我们提出了 Bcl-3 在通过 kappa B 位点通过抵消结合的抑制作用来促进反式激活的作用，NF-kappa B 的 p50 亚基的非反式激活同源二聚体。这种同源二聚体在例如未受刺激的初级细胞核中很丰富T细胞。在这里，我们扩展了模型并提供了满足许多预测的新证据。(i) Bcl-3 优先靶向 p50 同源二聚体而不是 NF-kappa B 异源二聚体，因为在不影响 NF-kappa B 的 Bcl-3 浓度下，同源二聚体与 kappa B 位点完全解离。 (ii) 选择 kappa B 位点非常相关与 p50 同源二聚体强烈而稳定地结合，完全阻止了 NF-kappa B 的结合。这样的 kappa B 位点可能是 p50 同源二聚体和 Bcl-3 调节的候选者。(iii) Bcl-3 和 p50 可以共定位在细胞核中，需要在体内从它们的结合位点主动去除同源二聚体。(iv) Bcl-3 的锚蛋白重复结构域足以逆转 p50 同源二聚体介导的抑制，这与该结构域在体外抑制 p50 与 kappa B 位点结合的能力有关。我们的数据支持在细胞刺激期间可能需要诱导核 Bcl-3 以从某些 kappa B 位点主动去除稳定结合的 p50 同源二聚体以允许反式激活 NF-kappa B 复合物参与的模型。体外实验证明了这种确切的机制。与该结构域在体外抑制 p50 与 kappa B 位点结合的能力相关。我们的数据支持在细胞刺激期间可能需要诱导核 Bcl-3 以从某些 kappa B 位点主动去除稳定结合的 p50 同源二聚体以允许反式激活 NF-kappa B 复合物参与的模型。体外实验证明了这种确切的机制。与该结构域在体外抑制 p50 与 kappa B 位点结合的能力相关。我们的数据支持在细胞刺激期间可能需要诱导核 Bcl-3 以从某些 kappa B 位点主动去除稳定结合的 p50 同源二聚体以允许反式激活 NF-kappa B 复合物参与的模型。体外实验证明了这种确切的机制。

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The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites.

Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappa B sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF-kappa B. Such homodimers are abundant for example in nuclei of unstimulated primary T cells. Here we extend the model and provide new evidence which fulfills a number of predictions. (i) Bcl-3 preferentially targets p50 homodimers over NF-kappa B heterodimers since the homodimers are completely dissociated from kappa B sites at concentrations of Bcl-3 which do not affect NF-kappa B. (ii) Select kappa B sites associate very strongly and stably with p50 homodimers, completely preventing binding by NF-kappa B. Such kappa B sites are likely candidates for regulation by p50 homodimers and Bcl-3. (iii) Bcl-3 and p50 can be co-localized in the nucleus, a requirement for active removal of homodimers from their binding sites in vivo. (iv) The ankyrin repeat domain of Bcl-3 is sufficient for the reversal of p50 homodimer-mediated inhibition, correlating with the ability of this domain alone to inhibit p50 binding to kappa B sites in vitro. Our data support the model that induction of nuclear Bcl-3 may be required during cellular stimulation to actively remove stably bound p50 homodimers from certain kappa B sites in order to allow transactivating NF-kappa B complexes to engage. This exact mechanism is demonstrated with in vitro experiments.

更新日期：2019-11-01

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