Identification of the molecular requirements for an RAR alpha-mediated cell cycle arrest during granulocytic differentiation.
Identification of the molecular requirements for an RAR alpha-mediated cell cycle arrest during granulocytic differentiation.
复制标题
粒细胞分化过程中 RAR α 介导的细胞周期停滞的分子需求的鉴定。
作者：
Carl R Walkley;L. Purton;Hayley J Snelling;Yang;H. Nakajima;P. Chambon;R. Chandraratna;G. McArthur
类维生素A是细胞周期停滞和多种细胞类型（特别是粒细胞）分化的有效诱导剂。然而，类维生素A在分化过程中介导细胞周期停滞的机制仍不清楚。我们使用骨髓分化来表征将细胞周期退出与终末分化耦合的分子途径。使用缺乏细胞周期蛋白依赖性激酶抑制剂 (CDKi) p27(Kip1)、Myc 拮抗剂 Mad1 或 Mad1 和 p27(Kip1) 的小鼠的原代细胞，我们观察到，通过视黄酸受体 α (RAR α) 而不是 RAR β 或 γ 介导的信号需要 Mad1 和 p27(Kip1) 来诱导细胞周期停滞并加速粒细胞的终末分化。虽然RAR α不直接调节Mad1或p27(Kip1)，但RAR α靶基因C/EBP epsilon直接调节Mad1的转录。粒细胞中 C/EBP epsilon 活性的诱导导致 Mad1 蛋白和转录物的快速诱导，通过染色质免疫沉淀测定证明 C/EBP epsilon 与 Mad1 启动子的直接结合。这些数据表明，响应 RAR α 的细胞周期停滞特别需要 Mad1 和 p27(Kip1)，并且 Mad1 由 CCAAT/增强子结合蛋白 epsilon (C/EBP epsilon) 转录激活。此外，这些数据证明了 RAR 对细胞周期停滞途径的选择性，并提供了将分化诱导和 Myc 拮抗剂 Mad1 的调节联系起来的直接机制。
Retinoids are potent inducers of cell cycle arrest and differentiation of numerous cell types, notably granulocytes. However the mechanisms by which retinoids mediate cell cycle arrest during differentiation remain unclear. We have used myeloid differentiation to characterize the molecular pathways that couple cell cycle withdrawal to terminal differentiation. Using primary cells from mice deficient for either the cyclin-dependent kinase inhibitor (CDKi) p27(Kip1), the Myc antagonist Mad1, or both Mad1 and p27(Kip1), we observed that signals mediated through retinoic acid receptor alpha (RAR alpha), but not RAR beta or gamma, required both Mad1 and p27(Kip1) to induce cell cycle arrest and to accelerate terminal differentiation of granulocytes. Although RAR alpha did not directly regulate Mad1 or p27(Kip1), the RAR alpha target gene C/EBP epsilon directly regulated transcription of Mad1. Induction of C/EBP epsilon activity in granulocytic cells led to rapid induction of Mad1 protein and transcript, with direct binding of C/EBP epsilon to the Mad1 promoter demonstrated through chromatin immunoprecipitation assay. These data demonstrate that cell cycle arrest in response to RAR alpha specifically requires Mad1 and p27(Kip1) and that Mad1 is transcriptionally activated by CCAAT/enhancer-binding protein epsilon (C/EBP epsilon). Moreover, these data demonstrate selectivity among the RARs for cell cycle arrest pathways and provide a direct mechanism to link differentiation induction and regulation of the Myc antagonist Mad1.
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影响因子：
20.3
作者：
Bao-Tran H. Truong;Young-Jin Lee;T. Lodie;Dorothy J. Park;D. Perrotti;N. Watanabe;H. Koeffler;H. Nakajima;D. Tenen;S. Kogan
通讯作者：
Bao-Tran H. Truong;Young-Jin Lee;T. Lodie;Dorothy J. Park;D. Perrotti;N. Watanabe;H. Koeffler;H. Nakajima;D. Tenen;S. Kogan
影响因子：
20.3
作者：
Nakajima, H;Ihle, JN
通讯作者：
Ihle, JN
DOI：
10.1073/pnas.94.2.569
发表时间：
1997-01-21
影响因子：
11.1
作者：
Zhang, DE;Zhang, P;Tenen, DG
通讯作者：
Tenen, DG
影响因子：
10.5
作者：
Liu, M;Lee, MH;Freedman, LP
通讯作者：
Freedman, LP
影响因子：
20.3
作者：
K. Robertson;B. Emami;S. Collins
通讯作者：
K. Robertson;B. Emami;S. Collins