Gfi-1 represses CDKN2B encoding p15INK4B through interaction with Miz-1
Gfi-1 represses CDKN2B encoding p15INK4B through interaction with Miz-1
复制标题
DOI：
10.1073/pnas.0804863106
复制
发表时间：
2009-02-03
影响因子：
11.1
通讯作者：
Dong, Fan
中科院分区：
文献类型：
--
作者：
Basu, Suchitra;Liu, Qingquan;Dong, Fan
Gfi-1是一种核锌指（ZF）转录抑制因子，在造血和内耳发育中起重要作用，并且已经涉及淋巴瘤的发生。Gfi-1通过直接结合其靶基因启动子中的共有DNA序列来抑制转录。我们在这里报告了另一种机制，Gfi-1抑制CDKN 2B编码p15（INK 4 B）。Gfi-1不直接与CDKN 2B结合，但与Miz-1相互作用，并通过Miz-1被募集到CDKN 2B的核心启动子。Miz-1是一种POZ-ZF转录因子，已显示其介导c-Myc的转录抑制。与c-Myc一样，在募集到CDKN 2B启动子后，Gfi-1通过Miz-1和响应于TGF β抑制CDKN 2B的转录激活。与其在抑制CDKN 2B转录中的作用一致，在人白血病细胞中Gfi-1的敲低或在小鼠骨髓细胞中Gfi-1的缺乏导致p15 INK 4 B的表达增加。值得注意的是，Gfi-1和c-Myc都被募集到CDKN 2B核心启动子，并协同作用以抑制CDKN 2B。我们的数据揭示了Gfi-1的转录抑制机制，可能对理解Gfi-1在正常发育和肿瘤发生中的作用具有重要意义。
Gfi-1 is a nuclear zinc finger (ZF) transcriptional repressor that plays an important role in hematopoiesis and inner ear development, and has been implicated in lymphomagenesis. Gfi-1 represses transcription by directly binding to the consensus DNA sequence in the promoters of its target genes. We report here an alternative mechanism by which Gfi-1 represses CDKN2B encoding p15(INK4B). Gfi-1 does not directly bind to CDKN2B, but interacts with Miz-1 and, via Miz-1, is recruited to the core promoter of CDKN2B. Miz-1 is a POZ-ZF transcription factor that has been shown to mediate transcriptional repression by c-Myc. Like c-Myc, upon recruitment to the CDKN2B promoter, Gfi-1 represses transcriptional activation of CDKN2B by Miz-1 and in response to TGF beta. Consistent with its role in repressing CDKN2B transcription, knockdown of Gfi-1 in human leukemic cells or deficiency of Gfi-1 in mouse bone marrow cells results in augmented expression of p15INK4B. Notably, Gfi-1 and c-Myc are both recruited to the CDKN2B core promoter and act in collaboration to repress CDKN2B. Our data reveal a mechanism of transcriptional repression by Gfi-1 and may have important implications for understanding the roles of Gfi-1 in normal development and tumorigenesis.