ErbB2 induces Notch1 activity and function in breast cancer cells.
ErbB2 induces Notch1 activity and function in breast cancer cells.
复制标题
DOI：
10.1111/j.1752-8062.2008.00041.x
复制
发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
Pestell RG
中科院分区：
文献类型：
--
作者：
Lindsay J;Jiao X;Sakamaki T;Casimiro MC;Shirley LA;Tran TH;Ju X;Liu M;Li Z;Wang C;Katiyar S;Rao M;Allen KG;Glazer RI;Ge C;Stanley P;Lisanti MP;Rui H;Pestell RG
ErbB 2（Her 2/neu表皮生长受体家族）癌基因在30%至40%的人类乳腺癌中过表达。细胞周期蛋白D1是磷酸化和灭活视网膜母细胞瘤（pRb）肿瘤抑制因子的全酶的调节亚基，是ErbB 2诱导的肿瘤生长的重要下游靶点。在此，我们证明了ErbB 2诱导Notch信号通路的活性。ErbB 2诱导DNA合成、非接触性生长和乳腺球诱导需要Notch 1。ErbB 2诱导的细胞周期蛋白D1和细胞周期蛋白D1的表达足以诱导Notch 1的活性，相反，使用floxed Notch（Notchfl/fl）小鼠的乳腺上皮细胞中Notch 1的基因缺失证明细胞周期蛋白D1由Notch 1诱导。基因缺失细胞周期蛋白D1或小干扰RNA（siRNA）的细胞周期蛋白D1减少Notch 1的活性和重新引入细胞周期蛋白D1到细胞周期蛋白D1缺陷的细胞恢复Notch 1的活性，通过抑制Numb，内源性抑制剂的Notch 1的活性。因此，细胞周期蛋白D1作为Notch 1的遗传靶点在下游发挥作用，通过抑制Numb来放大Notch 1的活性，并鉴定了ErbB 2通过诱导细胞周期蛋白D1来诱导Notch 1活性的新途径。
The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was sufficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using floxed Notch (Notchfl/fl ) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.
登录
查看更多内容
DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
5
作者：
Florena, Ada Maria;Tripodo, Claudio;Franco, Vito
通讯作者：
Franco, Vito
影响因子：
3.2
作者：
Aster, JC;Pear, WS
通讯作者：
Pear, WS
影响因子：
5.3
作者：
Ross, DA;Kadesch, T
通讯作者：
Kadesch, T
影响因子：
5.3
作者：
Imai, T;Tokunaga, A;Okano, H
通讯作者：
Okano, H