p300/CBP-associated factor drives DEK into interchromatin granule clusters
p300/CBP-associated factor drives DEK into interchromatin granule clusters
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DOI：
10.1074/jbc.m500884200
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发表时间：
2005-09-09
影响因子：
4.8
通讯作者：
Markovitz, DM
中科院分区：
文献类型：
--
作者：
Cleary, J;Sitwala, KV;Markovitz, DM
DEK是一种哺乳动物蛋白，其与自身免疫性疾病和癌症的发病机制有关，包括急性髓性白血病、黑素瘤、胶质母细胞瘤、肝细胞癌和膀胱癌。此外，DEK似乎参与多种细胞过程，包括转录抑制、mRNA加工和染色质重塑。这种蛋白质的亚核分布及其伴随的功能分支仍然是一个有争议的话题。在这里，我们报告，DEK在体内经历乙酰化在前70个N-末端氨基酸内的赖氨酸残基。乙酰化的DEK降低其对启动子内DNA元件的亲和力，这与DEK参与转录抑制一致。此外，去乙酰化酶抑制导致DEK在染色质间颗粒簇（IGCs）内积累，IGCs是含有RNA加工因子的亚核结构。P/CAF乙酰化酶的过表达驱动DEK进入IGCs，并且添加新开发的、合成的、细胞可渗透的P/CAF抑制剂阻断这种运动。据我们所知，这是第一个报道的乙酰化在蛋白质迁移到IGCs中发挥直接作用的例子，这可能解释了DEK如何在不同的亚核区室中发生的多个途径中发挥作用。这些发现还表明，DEK相关的恶性肿瘤和自身免疫性疾病可能适用于改变乙酰化的药物治疗。
DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters ( IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.