Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters.
Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters.
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DOI：
10.1371/journal.pone.0051205
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Williams CS
中科院分区：
文献类型：
--
作者：
Barrett CW;Smith JJ;Lu LC;Markham N;Stengel KR;Short SP;Zhang B;Hunt AA;Fingleton BM;Carnahan RH;Engel ME;Chen X;Beauchamp RD;Wilson KT;Hiebert SW;Reynolds AB;Williams CS
髓系易位基因(MTG)是最初在急性髓系白血病中发现的转录辅阻遏子，最近被发现与结肠癌、乳腺癌和肺癌中的MTG8和MTG16非同义突变有关，此外还可以作为WNT和Notch信号的负调控因子。采用酵母双杂交方法寻找新的MTG结合伙伴。本实验鉴定了含有ZBTB家族成员ZBTB4和ZBTB38的锌指、C2H2和BTB结构域为MTG16相互作用蛋白。ZBTB4在乳腺癌中表达下调，并调节P53的反应。由于ZBTB33(Kaiso)和MTG16一样，在TCF4水平上调节Wnt信号，并且它的缺失抑制了ApcMin小鼠的肠道肿瘤发生，我们确定Kaiso也与MTG16相互作用来调节转录。用免疫共沉淀法证实了Kaiso的锌指结构域以及ZBTB4和ZBTB38与MTG16结合并与Kaiso结合。MTG家族成员需要有效地抑制含有Kaiso结合位点的异源报告结构(4×kBS)和已知的Kaiso靶标--基质金属蛋白酶-7(MMP7/Matrilysin)。此外，染色质免疫沉淀研究将MTG16放置在占据MMP7启动子上Kaiso结合位置的复合体中。MTG16在这个复合体中的存在及其对转录抑制的贡献都需要Kaiso与其在DNA上的结合部位结合，从而建立了MTG16-Kaiso结合在Kaiso依赖的转录抑制中的功能相关。对一个大型的多阶段CRC表达阵列数据集的研究发现，Kaiso、MTG16和MMP-7的表达模式支持这样的假设，即Kaiso或MTG16的缺失可以解除对靶启动子的调控，例如MMP-7。这些发现为ZBTB家族成员的转录调控机制提供了新的见解，并拓宽了MTG家族的协同抑制功能的范围，表明Kaiso/MTG复合体在癌症中对转录的协调调节。
Myeloid translocation genes (MTGs) are transcriptional corepressors originally identified in acute myelogenous leukemia that have recently been linked to epithelial malignancy with non-synonymous mutations identified in both MTG8 and MTG16 in colon, breast, and lung carcinoma in addition to functioning as negative regulators of WNT and Notch signaling. A yeast two-hybrid approach was used to discover novel MTG binding partners. This screen identified the Zinc fingers, C2H2 and BTB domain containing (ZBTB) family members ZBTB4 and ZBTB38 as MTG16 interacting proteins. ZBTB4 is downregulated in breast cancer and modulates p53 responses. Because ZBTB33 (Kaiso), like MTG16, modulates Wnt signaling at the level of TCF4, and its deletion suppresses intestinal tumorigenesis in the ApcMin mouse, we determined that Kaiso also interacted with MTG16 to modulate transcription. The zinc finger domains of Kaiso as well as ZBTB4 and ZBTB38 bound MTG16 and the association with Kaiso was confirmed using co-immunoprecipitation. MTG family members were required to efficiently repress both a heterologous reporter construct containing Kaiso binding sites (4×KBS) and the known Kaiso target, Matrix metalloproteinase-7 (MMP-7/Matrilysin). Moreover, chromatin immunoprecipitation studies placed MTG16 in a complex occupying the Kaiso binding site on the MMP-7 promoter. The presence of MTG16 in this complex, and its contributions to transcriptional repression both required Kaiso binding to its binding site on DNA, establishing MTG16-Kaiso binding as functionally relevant in Kaiso-dependent transcriptional repression. Examination of a large multi-stage CRC expression array dataset revealed patterns of Kaiso, MTG16, and MMP-7 expression supporting the hypothesis that loss of either Kaiso or MTG16 can de-regulate a target promoter such as that of MMP-7. These findings provide new insights into the mechanisms of transcriptional control by ZBTB family members and broaden the scope of co-repressor functions for the MTG family, suggesting coordinate regulation of transcription by Kaiso/MTG complexes in cancer.
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影响因子：
8
作者：
Kim, K.;Chadalapaka, G.;Lee, S-O;Yamada, D.;Sastre-Garau, X.;Defossez, P-A;Park, Y-Y;Lee, J-S;Safe, S.
通讯作者：
Safe, S.
影响因子：
5.3
作者：
Moore, Amy C.;Amann, Joseph M.;Hiebert, Scott W.
通讯作者：
Hiebert, Scott W.
影响因子：
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作者：
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影响因子：
11.8
作者：
Park, JI;Kim, SW;McCrea, PD
通讯作者：
McCrea, PD
影响因子：
5.3
作者：
Liu, Dage;Nakano, Jun;Huang, Cheng-long
通讯作者：
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