p53 and ΔNp63α differentially bind and regulate target genes involved in cell cycle arrest, DNA repair and apoptosis
p53 and ΔNp63α differentially bind and regulate target genes involved in cell cycle arrest, DNA repair and apoptosis
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DOI：
10.1038/sj.onc.1210441
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发表时间：
2007-09-13
期刊：
影响因子：
8
通讯作者：
Pietenpol, J. A.
中科院分区：
文献类型：
--
作者：
Schavolt, K. L.;Pietenpol, J. A.
在各种类型的细胞应激后，p53蛋白家族协同调节选择的靶基因的机制尚不清楚。为了更进一步。决定靶基因调控的新因素，我们使用染色质免疫沉淀法检测了p53、Δ Np63 α和RNA聚合酶II（pol II）与原代人表皮角质形成细胞（HEK）中选定靶基因调控区的结合。在快速增殖的细胞中，我们观察到DNp63a和不同水平的p53结合的组成性结合，参与细胞周期阻滞，DNA修复和凋亡的靶基因的共识网站。遗传毒性应激后，p53占有率增加，而DNp63a占有率下降，在大多数结合位点检查。从异位表达p53和DNp63a的HEK中分离的转录物的微阵列分析揭示了两个家族成员对选择的靶基因的反向调节。总的来说，我们的研究结果表明，DNp63 a可以作为一个选择的p53靶基因参与生长停滞，DNA修复和细胞凋亡的阻遏物，并在靶基因的p53共识结合位点的位置可能会决定是否pol II是组成性结合在增殖细胞。
The mechanism by which the p53 family of proteins coordinately regulates select target genes after various types of cell stress is not well understood. To further de. ne factors that dictate regulation of target genes, we examined the binding of p53, Delta Np63 alpha and RNA polymerase II (pol II) to the regulatory regions of select target genes in primary human epidermal keratinocytes (HEKs) using chromatin immunoprecipitation. In rapidly proliferating cells, we observed constitutive binding of DNp63a and varying levels of p53 binding, to consensus sites in target genes involved in cell cycle arrest, DNA repair and apoptosis. Following genotoxic stress, p53 occupancy increased whereas DNp63a occupancy decreased at the majority of binding sites examined. Microarray analysis of transcripts isolated from HEKs ectopically expressing p53 and DNp63a revealed an inverse regulation of select target genes by the two family members. Collectively, our results suggest that DNp63a can function as a repressor of select p53 target genes involved in growth arrest, DNA repair and apoptosis, and that the location of the p53 consensus binding site(s) in a target gene may dictate whether pol II is constitutively bound in proliferating cells.