HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF
HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF
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DOI：
10.1038/sj.onc.1208128
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发表时间：
2004-11-18
期刊：
影响因子：
8
通讯作者：
Harel-Bellan, A
中科院分区：
文献类型：
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作者：
Chauchereau, A;Mathieu, M;Harel-Bellan, A
PLZF，早幼粒细胞白血病锌指蛋白，是一种发育所必需的转录抑制因子。在一些急性白血病中，将PLZF基因与编码视黄酸受体RAR α的基因融合的染色体易位产生融合蛋白PLZF RAR α，其被认为负责这些细胞中分化相关基因的组成性抑制。PLZF和PLZF-RAR α的抑制对组蛋白去乙酰化酶抑制剂TSA敏感，PLZF先前被证明与HDAC 1（一种I类组蛋白去乙酰化酶）发生物理相互作用。我们在此询问已知通常参与分化过程的II类组蛋白脱乙酰酶是否参与PLZF和PLZF-RAR α介导的抑制，并发现PLZF在GST-下拉和免疫共沉淀测定中与HDAC 4相互作用。此外，HDAC 4确实参与PLZF和PLZF-RAR α介导的阻遏，因为HDAC 4的酶促死亡突变体释放了阻遏，阻断HDAC 4表达的siRNA也是如此。总之，我们的数据表明，HDAC 4的招聘是必要的PLZF介导的抑制在正常和白血病细胞。
PLZF, the promyelocytic leukaemia zinc-finger protein, is a transcriptional repressor essential to development. In some acute leukaemias, a chromosomal translocation fusing the PLZF gene to that encoding the retinoic acid receptor RARalpha gives rise to a fusion protein, PLZF RARa, thought to be responsible for constitutive repression of differentiation-associated genes in these cells. Repression by both PLZF and PLZF-RARalpha is sensitive to the histone deacetylase inhibitor TSA, and PLZF was previously shown to interact physically with HDAC1, a class I histone deacetylase. We here asked whether class II histone deacetylases, known to be generally involved in differentiation processes, participate in the repression mediated by PLZF and PLZF-RARalpha, and found that PLZF interacts with HDAC4 in both GST-pull-down and co-immunoprecipitation assays. Furthermore, HDAC4 is indeed involved in PLZF and PLZF-RARalpha-mediated repression, since an enzymatically dead mutant of HDAC4 released the repression, as did an siRNA that blocks HDAC4 expression. Taken together, our data indicate that recruitment of HDAC4 is necessary for PLZF-mediated repression in both normal and leukaemic cells.