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MCP-1 趋化因子转录的 p53 调节。

Regulation of MCP-1 chemokine transcription by p53.

机构信息

Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Infektion und Krebs, Abteilung Virale Transformationsmechanismen, Heidelberg, Germany.

出版信息

Mol Cancer. 2010 Apr 20;9:82. doi: 10.1186/1476-4598-9-82.

DOI:10.1186/1476-4598-9-82
PMID:20406462
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2864217/
Abstract

BACKGROUND

Our previous studies showed that the expression of the monocyte-chemoattractant protein (MCP)-1, a chemokine, which triggers the infiltration and activation of cells of the monocyte-macrophage lineage, is abrogated in human papillomavirus (HPV)-positive premalignant and malignant cells. In silico analysis of the MCP-1 upstream region proposed a putative p53 binding side about 2.5 kb upstream of the transcriptional start. The aim of this study is to monitor a physiological role of p53 in this process.

RESULTS

The proposed p53 binding side could be confirmed in vitro by electrophoretic-mobility-shift assays and in vivo by chromatin immunoprecipitation. Moreover, the availability of p53 is apparently important for chemokine regulation, since TNF-alpha can induce MCP-1 only in human keratinocytes expressing the viral oncoprotein E7, but not in HPV16 E6 positive cells, where p53 becomes degraded. A general physiological role of p53 in MCP-1 regulation was further substantiated in HPV-negative cells harboring a temperature-sensitive mutant of p53 and in Li-Fraumeni cells, carrying a germ-line mutation of p53. In both cases, non-functional p53 leads to diminished MCP-1 transcription upon TNF-alpha treatment. In addition, siRNA directed against p53 decreased MCP-1 transcription after TNF-alpha addition, directly confirming a crosstalk between p53 and MCP-1.

CONCLUSION

These data support the concept that p53 inactivation during carcinogenesis also affects immune surveillance by interfering with chemokine expression and in turn communication with cells of the immunological compartment.

摘要

背景

我们之前的研究表明，趋化因子单核细胞趋化蛋白-1（MCP-1）的表达被阻断，该蛋白能触发单核细胞-巨噬细胞系细胞的浸润和激活，在人乳头瘤病毒（HPV）阳性的癌前和恶性细胞中。MCP-1 上游区域的计算机分析提出了一个假定的 p53 结合位点，大约在转录起始点上游 2.5kb 处。本研究的目的是监测 p53 在这个过程中的生理作用。

结果

通过电泳迁移率变动分析可以在体外证实假定的 p53 结合部位，通过染色质免疫沉淀可以在体内证实。此外，p53 的可用性显然对趋化因子的调节很重要，因为 TNF-α 只能诱导 HPV16 E7 表达的人类角质形成细胞中 MCP-1 的产生，而不能诱导 HPV16 E6 阳性细胞中 MCP-1 的产生，在 HPV16 E6 阳性细胞中，p53 被降解。在 HPV 阴性细胞中，p53 携带温度敏感型突变，在携带 p53 种系突变的 Li-Fraumeni 细胞中，进一步证实了 p53 在 MCP-1 调节中的一般生理作用。在这两种情况下，非功能性 p53 导致 TNF-α 处理后 MCP-1 转录减少。此外，针对 p53 的 siRNA 在添加 TNF-α 后降低了 MCP-1 的转录，直接证实了 p53 与 MCP-1 之间的相互作用。

结论

这些数据支持这样的概念，即在致癌过程中 p53 的失活也会通过干扰趋化因子的表达，并反过来与免疫细胞之间的通讯，影响免疫监视。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/5bc6b93cd1b6/1476-4598-9-82-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/ae9954a10860/1476-4598-9-82-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/f3ef34af3c86/1476-4598-9-82-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/f41f8cb04fd0/1476-4598-9-82-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/950a033c1766/1476-4598-9-82-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/5bc6b93cd1b6/1476-4598-9-82-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/ae9954a10860/1476-4598-9-82-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/f3ef34af3c86/1476-4598-9-82-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/f41f8cb04fd0/1476-4598-9-82-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/950a033c1766/1476-4598-9-82-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6e/2864217/5bc6b93cd1b6/1476-4598-9-82-5.jpg

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