THE ONCOPROTEIN BCL-3 CAN FACILITATE NF-THETA-B-MEDIATED TRANSACTIVATION BY REMOVING INHIBITING P50 HOMODIMERS FROM SELECT THETA-B SITES
THE ONCOPROTEIN BCL-3 CAN FACILITATE NF-THETA-B-MEDIATED TRANSACTIVATION BY REMOVING INHIBITING P50 HOMODIMERS FROM SELECT THETA-B SITES
复制标题
DOI：
10.1002/j.1460-2075.1993.tb06067.x
复制
发表时间：
1993-10-01
期刊：
影响因子：
11.4
通讯作者：
SIEBENLIST, U
中科院分区：
文献类型：
--
作者：
FRANZOSO, G;BOURS, V;SIEBENLIST, U
以前，我们已经提出了Bcl-3的作用，通过kappaB位点的反式激活促进抑制作用的约束，非反式激活同源二聚体的NF-κ B的p50亚基。此类同源二聚体例如在未刺激的原代T细胞的细胞核中是丰富的。在这里，我们扩展了模型，并提供了新的证据，实现了一些预测。(i)Bcl-3优先靶向p50同二聚体而不是NF-κ B异二聚体，因为在不影响NF-κ B的Bcl-3浓度下，同二聚体完全从κ B位点解离。(ii)选择kappaB位点与p50同源二聚体非常强烈和稳定地结合，完全阻止NF-κ B的结合。这些kappaB位点可能是p50同源二聚体和Bcl-3调控的候选者。(iii)Bcl-3和p50可以共定位在细胞核中，这是从其体内结合位点主动去除同源二聚体的要求。(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，这与该结构域单独抑制p50与kappaB位点体外结合的能力相关。我们的数据支持这样的模型，即在细胞刺激过程中可能需要诱导核Bcl-3，以主动从某些kappaB位点去除稳定结合的p50同源二聚体，从而允许反式激活NF-κ B复合物参与。这种确切的机制是在体外实验证明。
Previously we have proposed a role for Bcl-3 in facilitating transactivation through kappaB sites by counteracting the inhibitory effects of bound, non-transactivating homodimers of the p50 subunit of NF-kappaB. 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-kappaB heterodimers since the homodimers are completely dissociated from kappaB sites at concentrations of Bcl-3 which do not affect NF-kappaB. (ii) Select kappaB sites associate very strongly and stably with p50 homodimers, completely preventing binding by NF-kappaB. Such kappaB 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 kappaB 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 kappaB sites in order to allow transactivating NF-kappaB complexes to engage. This exact mechanism is demonstrated with in vitro experiments.