Limited role of N-terminal phosphoserine residues in the activation of transcription by p53
Limited role of N-terminal phosphoserine residues in the activation of transcription by p53
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DOI：
10.1038/sj.onc.1207575
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发表时间：
2004-05-27
期刊：
影响因子：
8
通讯作者：
Stark, GR
中科院分区：
文献类型：
--
作者：
Jackson, MW;Agarwal, MK;Stark, GR
p53肿瘤抑制因子响应于各种细胞应激信号（如DNA损伤）而磷酸化，导致其从MDM 2释放，并随后稳定和活化为转录因子。在人U2 OS细胞中，用阿霉素处理导致p53在测试的所有六个丝氨酸残基上被磷酸化，导致p53从MDM 2解离以及p21和mdm 2基因的转录。相反，在这些细胞中，IPTG依赖性诱导p14 ARF，将MDM 2与p53隔离，不会导致检测的五个N-末端丝氨酸残基中任何一个的可检测磷酸化（6，9，15，20，37）。只有C-末端丝氨酸392被磷酸化。然而，p21和mdm 2 mRNA的增加与阿霉素治疗或诱导p14 ARF后没有区别。通过使用cDNA阵列来检查全球p53依赖基因表达的阿霉素或p14 ARF，我们发现，大多数基因的调节相似的两种治疗。然而，一个子集的p53调节基因，其产品具有增殖作用或调节VEGF的活性，这里新描述的，抑制p14 ARF远远超过阿霉素。我们的结论是，p53的N-末端丝氨酸残基的磷酸化是不需要的绝大多数p53响应基因的转录增加，并通过p14 ARF的诱导p53，几乎没有磷酸化，导致大量的基因抑制，其产品在增殖中的作用。
The p53 tumor suppressor is phosphorylated in response to various cellular stress signals, such as DNA damage, leading to its release from MDM2 and consequent stabilization and activation as a transcription factor. In human U2OS cells, treatment with adriamycin causes p53 to be phosphorylated on all six serine residues tested, leading to the dissociation of p53 from MDM2 and transcription of the p21 and mdm2 genes. In contrast, in these cells, IPTG-dependent induction of p14ARF, which sequesters MDM2 away from p53, does not lead to detectable phosphorylation of any of the five N-terminal serine residues tested (6, 9, 15, 20, 37). Only C-terminal serine 392 is phosphorylated. However, the increase of p21 and mdm2 mRNAs was indistinguishable following treatment with adriamycin or induction of p14ARF. By using cDNA arrays to examine global p53-dependent gene expression in response to adriamycin or p14ARF, we found that most genes were regulated similarly by the two treatments. However, a subset of p53-regulated genes whose products have proliferative roles or regulate VEGF activity, newly described here, are repressed by p14ARF much more than by adriamycin. We conclude that the phosphorylation of p53 on N-terminal serine residues is not required for increased transcription of the great majority of p53-responsive genes and that the induction of p53 by p14ARF, with little phosphorylation, leads to substantial repression of genes whose products have roles in proliferation.