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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain
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BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain

机译：BRD4是一种非典型激酶，可磷酸化RNA聚合酶II羧基末端结构域的Serine2

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摘要

The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for meta-static breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papil-loma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription.
机译：溴结构域蛋白BRD4最近已被确认为急性髓细胞性白血病，多发性骨髓瘤，伯基特淋巴瘤，NUT中线癌，结肠癌和炎症性疾病的治疗靶点；它的丢失是转移性乳腺癌的预后标志。 BRD4还有助于调节细胞周期以及癌基因，HIV和人乳头瘤病毒（HPV）的转录。尽管其在广泛的生物学过程中起作用，但BRD4功能的确切分子机制仍然未知。我们报告说，BRD4是一种非典型激酶，可与RNA聚合酶II的羧基末端结构域（CTD）结合，并在其他CTD激酶失活的条件下在体外和体内直接磷酸化其丝氨酸2（Ser2）位点。 BRD4抑制剂在体内抑制CTD Ser2的磷酸化，该抑制剂可阻止其与染色质的结合。我们的发现表明BRD4是RNA聚合酶II CTD Ser2激酶，暗示它是真核转录的调节剂。

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    Ballachanda N. Devaiah; Brian A. Lewis; Natasha Cherman; Michael C. Hewitt; Brian K. Albrecht; Pamela G. Robey; Keiko Ozato; Robert J. Sims III; Dinah S. Singer;

  • 作者单位

    Experimental Immunology National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Metabolism Branches, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Craniofacial and Skeletal Diseases Branch National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;

    Constellation Pharmaceuticals, Inc., Cambridge, MA 02142;

    Constellation Pharmaceuticals, Inc., Cambridge, MA 02142;

    Craniofacial and Skeletal Diseases Branch National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;

    Laboratory of Molecular Growth Regulation, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;

    Constellation Pharmaceuticals, Inc., Cambridge, MA 02142;

    Experimental Immunology National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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