Specific inhibition of the transcription factor Ci by a cobalt(III) Schiff base-DNA conjugate.
Specific inhibition of the transcription factor Ci by a cobalt(III) Schiff base-DNA conjugate.
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DOI：
10.1021/mp2005577
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发表时间：
2012-02-06
影响因子：
4.9
通讯作者：
Meade TJ
中科院分区：
文献类型：
--
作者：
Hurtado RR;Harney AS;Heffern MC;Holbrook RJ;Holmgren RA;Meade TJ
我们描述了使用 Co(III) 席夫碱-DNA 缀合物（一种针对 C2H2 转录因子的多功能研究工具）来抑制 Hedgehog (Hh) 通路。在哺乳动物胚胎发育过程中，Hh 信号传导对于许多组织和器官的形成和发育至关重要。 Hedgehog (Hh) 通路的不当激活与多种癌症有关，包括髓母细胞瘤和基底细胞癌。众所周知，Hh 调节哺乳动物中 C2H2 锌指转录因子 Gli 家族的活性。在果蝇中，Gli 蛋白的功能由具有相同 DNA 结合共有序列的单个转录因子 Cubitus Interruptus (Ci) 执行。我们之前已经证明，特定的 17 个碱基对寡核苷酸与 Co(III) 希夫碱复合物的缀合会产生 Snail 家族 C2H2 锌指转录因子的靶向抑制剂。将 Co(III) 希夫碱-DNA 缀合物中的寡核苷酸序列修饰为 Ci 的共有序列 (Co(III)-Ci) 会生成具有同等选择性的 Ci 抑制剂。 Co(III)-Ci 不可逆地结合 Ci 锌指结构域并阻止其在体外结合 DNA。在 Ci 响应组织培养报告基因测定中，Co(III)-Ci 以浓度依赖性方式降低 Ci 的转录活性。此外，向野生型果蝇胚胎注射Co(III)-Ci表型复制了Ci功能丧失表型，证明了体内的有效性。这项研究提供的证据表明，Co(III) 席夫碱-DNA 缀合物是一类用于研究锌指结构域蛋白的多功能特异性且有效的工具，并且具有作为可定制抗癌疗法的潜在应用。
We describe the use of Co(III) Schiff base-DNA conjugates, a versatile class of research tools that target C2H2 transcription factors, to inhibit the Hedgehog (Hh) pathway. In developing mammalian embryos, Hh signaling is critical for the formation and development of many tissues and organs. Inappropriate activation of the Hedgehog (Hh) pathway has been implicated in a variety of cancers including medulloblastomas and basal cell carcinomas. It is well known that Hh regulates the activity of the Gli family of C2H2 zinc finger transcription factors in mammals. In Drosophila the function of the Gli proteins is performed by a single transcription factor with an identical DNA binding consensus sequence, Cubitus Interruptus (Ci). We have demonstrated previously that conjugation of a specific 17 base-pair oligonucleotide to a Co(III) Schiff base complex results in a targeted inhibitor of the Snail family C2H2 zinc finger transcription factors. Modification of the oligonucleotide sequence in the Co(III) Schiff base-DNA conjugate to that of Ci’s consensus sequence (Co(III)-Ci) generates an equally selective inhibitor of Ci. Co(III)-Ci irreversibly binds the Ci zinc finger domain and prevents it from binding DNA in vitro. In a Ci responsive tissue culture reporter gene assay, Co(III)-Ci reduces the transcriptional activity of Ci in a concentration dependent manner. In addition, injection of wild-type Drosophila embryos with Co(III)-Ci phenocopies a Ci loss of function phenotype, demonstrating effectiveness in vivo. This study provides evidence that Co(III) Schiff base-DNA conjugates are a versatile class of specific and potent tools for studying zinc finger domain proteins and have potential applications as customizable anti-cancer therapeutics.
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影响因子：
64.8
作者：
KINZLER, KW;RUPPERT, JM;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.1073/pnas.0906423106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Harney, Allison S.;Lee, Jiyoun;Meade, Thomas J.
通讯作者：
Meade, Thomas J.
影响因子：
5.3
作者：
KINZLER, KW;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
1.5
作者：
Klueg, KM;Alvarado, D;Duffy, JB
通讯作者：
Duffy, JB
影响因子：
56.9
作者：
Henikoff, S;Greene, EA;Hood, L
通讯作者：
Hood, L