The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes.
The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes.
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DOI：
10.1093/nar/gkv927
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发表时间：
2016-01-08
影响因子：
14.9
通讯作者：
Engeland K
中科院分区：
文献类型：
--
作者：
Fischer M;Quaas M;Steiner L;Engeland K
肿瘤抑制因子P53主要作为转录因子，通过激活和下调基因表达，导致细胞周期停滞或凋亡。P53通过最近发现的P53-p21-DREAM-CDE/CHR途径间接抑制CCNB2、KIF23和Plk4细胞周期基因的转录。然而，目前还不清楚这种途径是否常用。在这里，我们通过全基因组计算的方法确定由p53通过这一途径调控的基因。生物信息学分析基于全基因组的DREAM复合体结合数据、p53相关的mRNA表达数据和全基因组对系统发育保守的CHR启动子元件的定义。我们发现了210个预期受p53-p21-Dream-CDE/ChR通路调控的靶基因。通过对细胞周期基因B-MYB(MYBL2)、Bub1、Ccna2、CCNB1、CHEK2、Melk、POLD1、RAD18和RAD54L的详细分析，验证了靶基因清单的正确性。210个靶基因中的大多数都是G2期和有丝分裂的重要调节基因。因此，通过P53-p21-DREAM-CDE/CHR途径下调这些基因似乎是P53阻止G2/M细胞周期的主要机制。
The tumor suppressor p53 functions predominantly as a transcription factor by activating and downregulating gene expression, leading to cell cycle arrest or apoptosis. p53 was shown to indirectly repress transcription of the CCNB2, KIF23 and PLK4 cell cycle genes through the recently discovered p53-p21-DREAM-CDE/CHR pathway. However, it remained unclear whether this pathway is commonly used. Here, we identify genes regulated by p53 through this pathway in a genome-wide computational approach. The bioinformatic analysis is based on genome-wide DREAM complex binding data, p53-depedent mRNA expression data and a genome-wide definition of phylogenetically conserved CHR promoter elements. We find 210 target genes that are expected to be regulated by the p53-p21-DREAM-CDE/CHR pathway. The target gene list was verified by detailed analysis of p53-dependent repression of the cell cycle genes B-MYB (MYBL2), BUB1, CCNA2, CCNB1, CHEK2, MELK, POLD1, RAD18 and RAD54L. Most of the 210 target genes are essential regulators of G2 phase and mitosis. Thus, downregulation of these genes through the p53-p21-DREAM-CDE/CHR pathway appears to be a principal mechanism for G2/M cell cycle arrest by p53.