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人类癌细胞系表达一种DNA结合蛋白的干扰素调节因子家族的负转录调节因子。

Human cancer cell lines express a negative transcriptional regulator of the interferon regulatory factor family of DNA binding proteins.

作者信息

Petricoin E, David M, Fang H, Grimley P, Larner A C, Vande Pol S

机构信息

Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20892.

出版信息

Mol Cell Biol. 1994 Feb;14(2):1477-86. doi: 10.1128/mcb.14.2.1477-1486.1994.

DOI:10.1128/mcb.14.2.1477-1486.1994
PMID:8289823
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC358503/
Abstract

Members of the interferon regulatory factor (IRF) family of DNA binding transcription factors have roles in growth regulation, antiviral responses, and transcriptional induction of interferon (IFN)-activated early response genes. The IRF family member ISGF3 gamma is the DNA binding component of IFN-stimulated gene factor 3 (ISGF3), a multicomponent complex responsible for the stimulation of IFN-alpha-responsive genes. IFN-alpha-stimulated formation of ISGF3 and subsequent gene expression can be inhibited by phorbol esters or expression of the adenovirus E1A protein. We have investigated IFN signaling in human malignant tumor cell lines of the lung, colon, ovary, cervix, and hematopoietic organs and found some of these cells to be defective for IFN-alpha-induced formation of ISGF3. In many cases, an inhibitory activity termed transcriptional knockout (TKO) correlated with nonresponsiveness. TKO purified from a human papillomavirus-negative cervical carcinoma cell line has a molecular size of 19 kDa. The purified protein interacted with the ISGF3 gamma component of ISGF3, preventing binding of ISGF3 to DNA. Purified TKO displaced ISGF3 from its DNA binding site in vitro and prevented ISGF3 gamma, IRF-1, and IRF-2 from interacting with the IFN-stimulated response element. Partially purified TKO can also directly interact with ISGF3 gamma in the absence of DNA. This protein may be involved with the development of malignancies and the inability of IFN to exert its antiproliferative and antiviral effects.

摘要

干扰素调节因子（IRF）家族的DNA结合转录因子成员在生长调节、抗病毒反应以及干扰素（IFN）激活的早期反应基因的转录诱导中发挥作用。IRF家族成员ISGF3γ是干扰素刺激基因因子3（ISGF3）的DNA结合成分，ISGF3是一种多组分复合物，负责刺激IFN-α反应性基因。佛波酯或腺病毒E1A蛋白的表达可抑制IFN-α刺激的ISGF3形成及随后的基因表达。我们研究了人肺癌、结肠癌、卵巢癌、宫颈癌和造血器官恶性肿瘤细胞系中的IFN信号传导，发现其中一些细胞在IFN-α诱导的ISGF3形成方面存在缺陷。在许多情况下，一种称为转录敲除（TKO）的抑制活性与无反应性相关。从人乳头瘤病毒阴性的宫颈癌细胞系中纯化的TKO分子大小为19 kDa。纯化的蛋白与ISGF3的ISGF3γ成分相互作用，阻止ISGF3与DNA结合。纯化的TKO在体外将ISGF3从其DNA结合位点上置换下来，并阻止ISGF3γ、IRF-1和IRF-2与干扰素刺激反应元件相互作用。部分纯化的TKO在无DNA的情况下也能直接与ISGF3γ相互作用。这种蛋白可能与恶性肿瘤的发生发展以及IFN无法发挥其抗增殖和抗病毒作用有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/3a285000d1c6/molcellb00002-0625-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/cc092d681577/molcellb00002-0621-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/de132388f3e3/molcellb00002-0621-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/c731ae8fa090/molcellb00002-0622-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/efc53f178812/molcellb00002-0623-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/c7d5fa74587a/molcellb00002-0624-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/3a285000d1c6/molcellb00002-0625-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/cc092d681577/molcellb00002-0621-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/de132388f3e3/molcellb00002-0621-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/c731ae8fa090/molcellb00002-0622-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/efc53f178812/molcellb00002-0623-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/c7d5fa74587a/molcellb00002-0624-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/05f3/358503/3a285000d1c6/molcellb00002-0625-a.jpg

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本文引用的文献

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Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase.佛波酯对α干扰素而非γ干扰素信号转导的抑制作用是由一种酪氨酸磷酸酶介导的。
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