Cyclin D1 integrates estrogen-mediated DNA damage repair signaling.
Cyclin D1 integrates estrogen-mediated DNA damage repair signaling.
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DOI：
10.1158/0008-5472.can-13-3137
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发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Pestell RG
中科院分区：
文献类型：
--
作者：
Li Z;Chen K;Jiao X;Wang C;Willmarth NE;Casimiro MC;Li W;Ju X;Kim SH;Lisanti MP;Katzenellenbogen JA;Pestell RG
细胞周期蛋白D1基因编码磷酸化视网膜母细胞瘤蛋白（pRb）和核呼吸因子（NRF 1）蛋白的全酶的调节亚基。细胞周期蛋白D1的丰度决定了小鼠乳腺中雌激素依赖性基因的表达。使用雌二醇（E2）和E2-树枝状聚合物的共轭物，这是从核中排除，我们证明E2延迟DNA损伤反应（DDR）通过一个双核机制。E2诱导的DDR需要胞核内cyclin D1与ERα结合，增加AKT磷酸化（Ser 473）和γ H2 AX灶的形成。在细胞核中，E2抑制，而细胞周期蛋白D1增强，同源定向DNA修复。Cyclin D1被E2募集到γ H2 AX灶并诱导Rad 51表达。细胞周期蛋白D1通过一种新的细胞核功能在E2依赖的DNA损伤反应中起重要作用。可分离的细胞质功能，以延迟E2介导的DDR与DNA修复的核增强一起揭示了一种新的细胞周期蛋白D1的核功能，可能有助于E2在乳腺肿瘤发生中的作用。
The cyclin D1 gene encodes the regulatory subunit of a holoenyzme that phosphorylates the retinoblastoma protein (pRb) and nuclear respiratory factor (NRF1) proteins. The abundance of cyclin D1 determines estrogen-dependent gene expression in the mammary gland of mice. Using estradiol (E2) and an E2-dendrimer conjugate which is excluded from the nucleus, we demonstrate E2 delays the DNA damage response (DDR) via an extranuclear mechanism. The E2-induced DDR required extranuclear cyclin D1 which bound ERα at the cytoplasmic membrane and augmented AKT phosphorylation (Ser473) and γH2AX foci formation. In the nucleus E2 inhibited, whereas cyclin D1 enhanced, homology directed DNA repair. Cyclin D1 was recruited to γH2AX foci by E2 and induced Rad51 expression. Cyclin D1 governs an essential role in the E2-dependent DNA-damage response via a novel extranuclear function. The dissociable cytoplasmic function to delay the E2 mediated-DDR together with the nuclear enhancement of DNA repair uncovers a novel extranuclear function of cyclin D1 that may contribute to the role of E2 in breast tumorigenesis.