RNA interference against mixed lineage leukemia 5 resulted in cell cycle arrest
RNA interference against mixed lineage leukemia 5 resulted in cell cycle arrest
复制标题
DOI：
10.1016/j.biocel.2008.04.012
复制
发表时间：
2008-01-01
影响因子：
4
通讯作者：
Deng, Lih-Wen
中科院分区：
文献类型：
--
作者：
Chang, Fei;Liu, Jie;Deng, Lih-Wen
混合谱系白血病5（MLL 5）编码位于染色体带7 q22内的哺乳动物三胸组（TrxG）蛋白，这是在急性髓系恶性肿瘤中发现的频繁缺失区域。三胸和多梳（PcG）组蛋白是进化上保守的转录调控因子，在发育过程中维持同源框（HOX）基因在表观遗传水平上的表达。最近，TrxG和PcG组蛋白在细胞周期调控中的新兴作用已开始被阐明。在这项研究中，我们证明了哺乳动物的trxG蛋白MLL 5参与多个细胞周期调控。通过小干扰RNA敲低MLL 5导致多个肿瘤和正常二倍体细胞中细胞生长迟缓和BrdU摄入减弱。通过敲低MLL 5诱导的细胞周期停滞发生在G1和G2/M期。在p53基因敲除的细胞系中也发现了这种生长抑制作用和双相阻滞，这表明p53的反式激活活性对于MLL 5基因敲除介导的细胞周期阻滞是无效的。此外，无论p53状态如何，在所有检测的细胞系中均观察到细胞周期蛋白依赖性激酶抑制剂p21的上调和视网膜母细胞瘤蛋白的去磷酸化。总之，我们的数据表明，MLL 5的沉默导致p21的上调和pRb的去磷酸化，这至少部分地有助于G1期和G2/M期阻滞。这些发现提供了证据，MLL 5可能是一个重要的细胞周期调节因子，参与细胞周期的多个阶段的细胞周期调控网络机制。(C)2008爱思唯尔有限公司保留所有权利。
Mixed lineage leukemia 5 (MLL5) encodes a mammalian trithorax group (TrxG) protein located within chromosome band 7q22, which is a frequently deleted region found in acute myeloid malignancies. Trithorax and polycomb (PcG)group proteins are evolutionarily conserved transcriptional regulators that maintain the expression of Homeobox (HOX) genes at the epigenetic level during development. Recently, the emerging roles of TrxG and PcG group proteins in cell cycle regulation have begun to be elucidated. In this study, we demonstrated that the mammalian trxG protein MLL5 is involved in multiple cell cycle regulation. Knockdown of MLL5 by small interfering RNA resulted in the retarded cell growth and attenuated intake of BrdU in multiple tumor and normal diploid cells. The cell cycle arrest induced by knockdown of MLL5 took place at both the G I and G2/M phases. This growth-inhibitory effect and dual-phase arrest were also found in p53-knockout cell lines, suggesting that the transactivation activity of p53 was dispensable for the MLL5-knockdown-mediated cell cycle arrest. In addition, up-regulation of cyclin-dependent kinase inhibitor p21 and dephosphorylation of retinoblastoma protein were observed in all cell lines tested regardless of their p53 status. Taken together, our data suggest that silencing of MLL5 leads to upregulation of p21 and dephosphorylation of pRb, which at least partially contributes to the G1 phase and G2/M phase arrest. These findings provide evidence that MLL5 might be an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages. (C) 2008 Elsevier Ltd. All rights reserved.