MOZ-TIF2 alters cofactor recruitment and histone modification at the RARβ2 promoter -: Differential effects of MOZ fusion proteins on CBP- AND MOZ-dependent activators
MOZ-TIF2 alters cofactor recruitment and histone modification at the RARβ2 promoter -: Differential effects of MOZ fusion proteins on CBP- AND MOZ-dependent activators
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DOI：
10.1074/jbc.m602633200
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发表时间：
2006-06-23
影响因子：
4.8
通讯作者：
Heery, David M.
中科院分区：
文献类型：
--
作者：
Collins, Hilary M.;Kindle, Karin B.;Heery, David M.
MOZ-TIF2 和 MOZ-CBP 是与治疗诱导的急性髓系白血病相关的致白血病融合蛋白。这些蛋白质被认为会破坏分化造血祖细胞中的正常基因表达。我们之前已经证明 MOZ-TIF2 通过 CREB 结合蛋白 (CBP)/p300 依赖性激活剂（例如核受体和 p53）抑制转录。在这里，我们发现 MOZ-TIF2 在体内与 RAR beta 2 启动子相关，导致 CBP/p300 募集改变、组蛋白修饰异常以及 RAR beta 2 基因下调。相反，MOZ-TIF2 上调由 MOZ/MYST3 依赖性激活剂 AML1/RUNX1 介导的转录。野生型 MOZ 和 MOZ-TIF2 均被发现与 AML1 共定位，并且 MOZ-TIF2 被招募到 AML1 靶启动子上。 MOZ-CBP 融合蛋白表现出与 MOZ-TIF2 相似的功能，即抑制视黄酸受体介导的转录，但增强 AML1 报告基因的激活。尽管它包含几乎整个 CBP 序列，但 MOZ-CBP 似乎与 PML 体没有关联。总之，我们的结果表明，致白血病 MOZ 融合蛋白对 CBP 依赖性和 MOZ 依赖性激活剂的活性具有不同的影响，因为它们能够改变目标启动子处的辅因子募集和染色质修饰。
MOZ-TIF2 and MOZ-CBP are leukemogenic fusion proteins associated with therapy-induced acute myeloid leukemia. These proteins are thought to subvert normal gene expression in differentiating hematopoietic progenitor cells. We have previously shown that MOZ-TIF2 inhibits transcription by CREB-binding protein (CBP)/p300-dependent activators such as nuclear receptors and p53. Here we have shown that MOZ-TIF2 associates with the RAR beta 2 promoter in vivo, resulting in altered recruitment of CBP/p300, aberrant histone modification, and down-regulation of the RAR beta 2 gene. In contrast, MOZ-TIF2 up-regulated transcription mediated by the MOZ/MYST3-dependent activator AML1/RUNX1. Both wild type MOZ and MOZ-TIF2 were found to colocalize with AML1, and MOZ-TIF2 was recruited to an AML1 target promoter. A MOZ-CBP fusion protein showed similar functions to MOZ-TIF2 in that it inhibited retinoic acid receptor-mediated transcription but enhanced AML1 reporter activation. Although it contains almost the entire CBP sequence, MOZ-CBP does not appear to associate with PML bodies. In summary, our results indicate that leukemogenic MOZ fusion proteins have differential effects on the activities of CBP-dependent and MOZ-dependent activators because of their ability to alter cofactor recruitment and chromatin modification at target promoters.