RelB/p52 NF-κB complexes rescue an early delay in mammary gland development in transgenic mice with targeted superrepressor IκB-α expression and promote carcinogenesis of the mammary gland
RelB/p52 NF-κB complexes rescue an early delay in mammary gland development in transgenic mice with targeted superrepressor IκB-α expression and promote carcinogenesis of the mammary gland
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DOI：
10.1128/mcb.25.22.10136-10147.2005
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发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Sonenshein, GE
中科院分区：
文献类型：
--
作者：
Demicco, EG;Kavanagh, KT;Sonenshein, GE
经典 NF-kappa B (p65/p50) 转录因子在怀孕期间在乳腺中表现出动态诱导。为了进一步阐明 NF-κ B 因子在乳腺发育中的作用，我们培育了一种转基因小鼠，在小鼠乳腺肿瘤病毒 (MMTV) 长末端重复启动子的控制下表达 Iκ B-α S32/36A 超阻遏物 (SR) 蛋白。在妊娠早期 5.5 天（d5.5）和 d7.5 的 MMTV-SR-I kappa B-alpha 小鼠中观察到乳腺导管分支短暂延迟；然而，发育在怀孕中后期恢复（d14.5）。恢复与核细胞周期蛋白 D1 和 RelB/p52 NF-kappa B 复合物的诱导相关。 RelB/p52 复合物诱导细胞周期蛋白 D1 和 c-myc 启动子活性，但在电泳迁移率变动测定中未能与 I kappa B-α-谷胱甘肽 S-转移酶相互作用，表明它们与 I kappa B-α 的弱相互作用可以解释观察到的乳腺发育的恢复。 d5.5 检测到 IKK α 和 NF-κ B 诱导激酶的激活，表明 RelB/p52 诱导中存在替代 NF-κ B 信号通路。在未转化的乳腺上皮细胞中，组成型活性 IKK α 诱导 p52、Refill 和细胞周期蛋白 D1。此外，7,12-二甲基苯并(a)蒽治疗诱导的小鼠乳腺肿瘤显示出 RelB/p52 活性增加。乳腺癌细胞中 RelB 的抑制可抑制细胞周期蛋白 D1 和 c-Myc 水平以及软琼脂中的生长。这些结果表明 RelB/p52 复合物参与乳腺发育和癌变。
Classical NF-kappa B (p65/p50) transcription factors display dynamic induction in the mammary gland during pregnancy. To further elucidate the role of NF-kappa B factors in breast development, we generated a transgenic mouse expressing the I kappa B-alpha S32/36A superrepressor (SR) protein under control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. A transient delay in mammary ductal branching was observed in MMTV-SR-I kappa B-alpha mice early during pregnancy at day 5.5 (d5.5) and d7.5; however, development recovered by mid- to late pregnancy (d14.5). Recovery correlated with induction of nuclear cyclin D1 and RelB/p52 NF-kappa B complexes. RelB/p52 complexes induced cyclin D1 and c-myc promoter activities and failed in electrophoretic mobility shift assay to interact with I kappa B-alpha-glutathione S-transferase, indicating that their weak interaction with I kappa B-alpha can account for the observed recovery of mammary gland development. Activation of IKK alpha and NF-kappa B-inducing kinase was detected by d5.5, implicating the alternative NF-kappa B signaling pathway in RelB/p52 induction. Constitutively active IKK alpha induced p52, Refill, and cyclin D1 in untransformed mammary epithelial cells. Moreover, mouse mammary tumors induced by 7,12-dimethylbenz(a)anthracene treatment displayed increased RelB/p52 activity. Inhibition of RelB in breast cancer cells repressed cyclin D1 and c-Myc levels and growth in soft agar. These results implicate RelB/p52 complexes in mammary gland development and carcinogenesis.