A role of Miz-1 in Gfi-1-mediated transcriptional repression of CDKN1A.
A role of Miz-1 in Gfi-1-mediated transcriptional repression of CDKN1A.
复制标题
DOI：
10.1038/onc.2010.48
复制
发表时间：
2010-05-13
期刊：
影响因子：
8
通讯作者：
Dong, F.
中科院分区：
文献类型：
--
作者：
Liu, Q.;Basu, S.;Qiu, Y.;Tang, F.;Dong, F.
锌指转录抑制因子Gfi-1在造血和内耳发育中起重要作用，同时也是一种与c-Myc共同参与淋巴瘤发生的癌蛋白。Gfi-1通过直接结合其靶基因启动子中的保守序列来抑制转录。编码p21 Cip 1的CDKN 1A已被鉴定为Gfi-1靶基因，并显示在上游启动子区含有Gfi-1结合位点。我们在这里表明，Gfi-1抑制CDKN 1A的方式是独立的DNA结合活性。Gfi-1与POZ-ZF转录因子Miz-1相互作用，最初显示为c-Myc相互作用伴侣，并通过Miz-1结合CDKN 1A核心启动子。有趣的是，Gfi-1和c-Myc通过Miz-1在CDKN 1A启动子上形成三元复合物，并协同作用抑制CDKN 1A。Gfi-1敲低导致p21 Cip 1水平提高和细胞增殖减弱。值得注意的是，与c-Myc类似，Gfi-1的表达被TGFβ下调，并且Gfi-1的水平影响细胞对TGFβ的细胞抑制作用的反应。我们的数据揭示了Gfi-1调节细胞增殖的重要机制，也可能对理解Gfi-1在淋巴瘤发生中的作用有影响。
Zinc-finger (ZF) transcriptional repressor Gfi-1 plays an important role in hematopoiesis and inner ear development, and also functions as an oncoprotein that cooperates with c-Myc in lymphomagenesis. Gfi-1 represses transcription by directly binding to conserved sequences in the promoters of its target genes. CDKN1A encoding p21Cip1 has been identified as a Gfi-1 target gene and shown to contain Gfi-1 binding sites in the upstream promoter region. We show here that Gfi-1 represses CDKN1A in a manner that is independent of its DNA binding activity. Gfi-1 interacts with POZ-ZF transcription factor Miz-1, originally shown to be a c-Myc interacting partner, and via Miz-1 binds to CDKN1A core promoter. Interestingly, Gfi-1 and c-Myc, through Miz-1, form a ternary complex on the CDKN1A promoter, and act in collaboration to repress CDKN1A. Gfi-1 knockdown results in enhanced levels of p21Cip1 and attenuated cell proliferation. Notably, similar to c-Myc, the expression of Gfi-1 is downregulated by TGFβ and the level of Gfi-1 influences the response of cell to the cytostatic effect of TGFβ. Our data reveal an important mechanism by which Gfi-1 regulates cell proliferation and may also have implications for understanding the role of Gfi-1 in lymphomagenesis.
登录
查看更多内容
DOI：
10.1073/pnas.0804863106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Basu, Suchitra;Liu, Qingquan;Dong, Fan
通讯作者：
Dong, Fan
影响因子：
5.3
作者：
GILKS, CB;BEAR, SE;TSICHLIS, PN
通讯作者：
TSICHLIS, PN
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
8
作者：
Lin, HK;Bergmann, S;Pandolfi, PP
通讯作者：
Pandolfi, PP
影响因子：
5.4
作者：
Scheijen, B;Jonkers, J;Berns, A
通讯作者：
Berns, A