Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors:: The case of HIC-1 and γFBP-B
Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors:: The case of HIC-1 and γFBP-B
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DOI：
10.1073/pnas.96.26.14831
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发表时间：
1999-12-21
影响因子：
11.1
通讯作者：
Leprince, D
中科院分区：
文献类型：
--
作者：
Deltour, S;Guerardel, C;Leprince, D
癌症中的高甲基化 (HIC-1) 是一种位于 17p13.3 的新候选肿瘤抑制基因，编码具有五个 C2H2 锌指和 N 末端宽复合物、tramtrack 的蛋白质，以及在参与染色质建模的肌动蛋白结合蛋白或转录调节因子中发现的bric a brac/痘病毒和锌指 (BTB/POZ) 结构域。在人 B 细胞淋巴瘤 (BCL-6) 和早幼粒细胞白血病 (PLZF) 癌蛋白中，该结构域通过招募类视黄醇和甲状腺激素受体 (SMRT)/核受体辅阻遏物 (N-CoR)-mSin3A-组蛋白脱乙酰酶 (HDAC) 复合物的沉默介质的能力来介导转录抑制，这是一种与许多转录因子共享的机制。 HIC-1 显得独特，因为它包含在进化后期获得的 13 个氨基酸插入，因为在其鸟类同源物 γ F1 结合蛋白亚型 B (γ FBP-B)（γ f-晶状体蛋白基因的转录抑制因子）中未发现它。该插入位于涉及 BTB/POZ 结构域二聚化和支架的保守区域，主要影响 HIC-1 和 γ FBP-B BTB/POZ 结构域在体内同源和异源二聚化的能力，如哺乳动物双杂交实验所示。 HIC-1 和 gamma FBP-B BTB/POZ 结构域均表现为自主转录抑制结构域。然而，与此形成鲜明对比的是：对于 BCL-6 和 PLZF，HIC-1 和 γ FBP-B 同样无法在体内和体外与 HDAC 复合体成员（SMRT/N-CoR、mSin3A 或 HDAC-1）相互作用。此外，HDAC 的通用和特异性抑制剂曲古抑菌素 A 并不能减轻 HIC-1 和 γ FBP-B 介导的转录抑制，如之前针对 BCL-6 所示。综上所述，我们的研究表明，招募到 HDAC 复合物的靶启动子上并不是包含保守 BTB/POZ 结构域的转录抑制子的一般特性。
Hypermethylated in cancer (HIC-1), a new candidate tumor suppressor gene located in 17p13.3, encodes a protein with five C2H2 zinc fingers and an N-terminal broad complex, tramtrack, and bric a brac/poxviruses and zinc-finger (BTB/POZ) domain found in actin binding proteins or transcriptional regulators involved in chromatin modeling. In the human B cell lymphoma (BCL-6) and promyelocityc leukemia (PLZF) oncoproteins, this domain mediates transcriptional repression through its ability to recruit a silencing mediator of retinoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor (N-CoR)-mSin3A-histone deacetylase (HDAC) complex, a mechanism shared with numerous transcription factors. HIC-1 appears unique because it contains a 13-aa insertion acquired late in evolution, because it is not found in its avian homologue, gamma F1-binding protein isoform B (gamma FBP-B), a transcriptional repressor of the gamma f-crystallin gene. This insertion, located in a conserved region involved in the dimerization and scaffolding of the BTB/POZ domain, mainly affects slightly the ability of the HIC-1 and gamma FBP-B BTB/POZ domains to homo- and heterodimerize in vivo, as shown by mammalian two-hybrid experiments. Both the HIC-1 and gamma FBP-B BTB/POZ domains behave as autonomous transcriptional repression domains. However, in striking contrast: with BCL-6 and PLZF, both HIC-1 and gamma FBP-B similarly fail to interact with members of the HDAC complexes (SMRT/N-CoR, mSin3A or HDAC-1) in vivo and in vitro. In addition, a general and specific inhibitor of HDACs, trichostatin A, did not alleviate the HIC-1- and gamma FBP-B-mediated transcriptional repression, as previously shown for BCL-6. Taken together, our studies show that the recruitment onto target promoters of an HDAC complex is not a general property of transcriptional repressors containing a conserved BTB/POZ domain.