Cyclin D-CDK4 relieves cooperative repression of proliferation and cell cycle gene expression by DREAM and RB.,Oncogene

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Cyclin D-CDK4 relieves cooperative repression of proliferation and cell cycle gene expression by DREAM and RB.
Oncogene ( IF 6.9 ) Pub Date : 2019-03-04 , DOI: 10.1038/s41388-019-0767-9
Amy E Schade _{1,

2} , Matthew G Oser _{2,

3} , Hilary E Nicholson ₂ , James A DeCaprio _{1,

2,

3}

Affiliation

The retinoblastoma protein (RB) restricts cell cycle gene expression and entry into the cell cycle. The RB-related protein p130 forms the DREAM (DP, RB-like, E2F, and MuvB) complex and contributes to repression of cell cycle-dependent genes during quiescence. Although both RB and DREAM bind and repress an overlapping set of E2F-dependent gene promoters, it remains unclear whether they cooperate to restrict cell cycle entry. To test the specific contributions of RB and DREAM, we generated RB and p130 knockout cells in primary human fibroblasts. Knockout of both p130 and RB yielded higher levels of cell cycle gene expression in G0 and G1 cells compared to cells with knockout of RB alone, indicating a role for DREAM and RB in repression of cell cycle genes. We observed that RB had a dominant role in E2F-dependent gene repression during mid to late G1 while DREAM activity was more prominent during G0 and early G1. Cyclin D-Cyclin-Dependent Kinase 4 (CDK4)-dependent phosphorylation of p130 occurred during early G1, and led to the release of p130 and MuvB from E2F4 and decreased p130 and MuvB binding to cell cycle promoters. Specific inhibition of CDK4 activity by palbociclib blocked DREAM complex disassembly during cell cycle entry. In addition, sensitivity to CDK4 inhibition was dependent on RB and an intact DREAM complex in both normal cells as well as in palbociclib-sensitive cancer cell lines. Although RB knockout cells were partially resistant to CDK4 inhibition, RB and p130 double knockout cells were significantly more resistant to palbociclib treatment. These results indicate that DREAM cooperates with RB in repressing E2F-dependent gene expression and cell cycle entry and supports a role for DREAM as a therapeutic target in cancer.

中文翻译：

Cyclin D-CDK4 减轻 DREAM 和 RB 对增殖和细胞周期基因表达的协同抑制。

视网膜母细胞瘤蛋白 (RB) 限制细胞周期基因表达和进入细胞周期。RB 相关蛋白 p130 形成 DREAM（DP、RB 样、E2F 和 MuvB）复合物，并有助于在静止期间抑制细胞周期依赖性基因。尽管 RB 和 DREAM 都结合并抑制一组重叠的 E2F 依赖性基因启动子，但尚不清楚它们是否合作限制细胞周期进入。为了测试 RB 和 DREAM 的具体贡献，我们在原代人成纤维细胞中生成了 RB 和 p130 敲除细胞。与单独敲除 RB 的细胞相比，敲除 p130 和 RB 在 G0 和 G1 细胞中产生更高水平的细胞周期基因表达，表明 DREAM 和 RB 在抑制细胞周期基因中的作用。我们观察到 RB 在 G1 中后期在 E2F 依赖性基因抑制中起主导作用，而 DREAM 活动在 G0 和 G1 早期更为突出。p130 的 Cyclin D-Cyclin-Dependent Kinase 4 (CDK4) 依赖性磷酸化发生在 G1 早期，导致 p130 和 MuvB 从 E2F4 释放，并减少 p130 和 MuvB 与细胞周期启动子的结合。palbociclib 对 CDK4 活性的特异性抑制阻断了细胞周期进入过程中 DREAM 复合物的分解。此外，对 CDK4 抑制的敏感性取决于正常细胞和对 palbociclib 敏感的癌细胞系中的 RB 和完整的 DREAM 复合物。尽管 RB 敲除细胞对 CDK4 抑制有部分抗性，但 RB 和 p130 双敲除细胞对 palbociclib 治疗的抗性明显更强。

更新日期：2019-03-04

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