GAM/ZFp/ZNF512B is central to a gene sensor circuitry involving cell-cycle regulators, TGF{beta} effectors, Drosha and microRNAs with opposite oncogenic potentials.
GAM/ZFp/ZNF512B is central to a gene sensor circuitry involving cell-cycle regulators, TGF{beta} effectors, Drosha and microRNAs with opposite oncogenic potentials.
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DOI：
10.1093/nar/gkq637
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发表时间：
2010-11
影响因子：
14.9
通讯作者：
Croce CM
中科院分区：
文献类型：
--
作者：
Tili E;Michaille JJ;Liu CG;Alder H;Taccioli C;Volinia S;Calin GA;Croce CM
microRNA（miRNAs）是一类靶向调节细胞稳态和发育的小分子RNA，其功能障碍与癌症等主要病理学相关。在此，我们发现GAM/ZFp/ZNF 512 B在一个复杂的基因调控网络中起作用，该网络涉及细胞周期调节因子、TGFβ效应子和miR-17-92簇的致癌miRNA。因此，GAM削弱c-Myc对miR-17-92启动子的转录激活，差异性地下调miR-17-92 miRNA，并限制响应于TGFβ经典途径的基因的激活。相比之下，TGFβ降低GAM转录水平，同时差异性上调miR-17-92 miRNA。反过来，miR-17、miR-20 a和miR-92 a-1靶向GAM转录物，从而建立反馈自动调节环。GAM转录物也被let-7家族的miRNA靶向。GAM下调Drosha，细胞核中miRNA成熟的主要效应子，并以RNA依赖的方式与其相互作用。最后，GAM调节E2 F1和Ras的水平，并增加细胞凋亡，同时减少细胞增殖。我们建议，GAM代表了一种新的脊椎动物调节器，旨在通过增加控制细胞增殖，分化和发育的基因电路的鲁棒性来平衡细胞稳态调节器的相反作用。
MicroRNAs (miRNAs) are small regulatory RNAs targeting multiple effectors of cell homeostasis and development, whose malfunctions are associated with major pathologies such as cancer. Herein we show that GAM/ZFp/ZNF512B works within an intricate gene regulatory network involving cell-cycle regulators, TGFβ effectors and oncogenic miRNAs of the miR-17-92 cluster. Thus, GAM impairs the transcriptional activation of the miR-17-92 promoter by c-Myc, downregulates miR-17-92 miRNAs differentially, and limits the activation of genes responsive to TGFβ canonical pathway. In contrast, TGFβ decreases GAM transcripts levels while differentially upregulating miR-17-92 miRNAs. In turn, miR-17, miR-20a and miR-92a-1 target GAM transcripts, thus establishing a feedback autoregulatory loop. GAM transcripts are also targeted by miRNAs of the let-7 family. GAM downregulates Drosha, the main effector of miRNA maturation in the nucleus, and interacts with it in a RNA-dependent manner. Finally, GAM modulates the levels of E2F1 and Ras, and increases apoptosis while reducing cell proliferation. We propose that GAM represents a new kind of vertebrate regulator aimed at balancing the opposite effects of regulators of cell homeostasis by increasing the robustness of gene circuitries controlling cell proliferation, differentiation and development.
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影响因子：
10.3
作者：
BENZ, CC;SCOTT, GK;SMITH, HS
通讯作者：
SMITH, HS
影响因子：
2.7
作者：
Lu, Yun;Thomson, J. Michael;Hogan, Brigid L. M.
通讯作者：
Hogan, Brigid L. M.
影响因子：
2
作者：
Akao, Yukihiro;Nakagawa, Yoshihito;Naoe, Tomoki
通讯作者：
Naoe, Tomoki
影响因子：
64.8
作者：
O'Donnell, KA;Wentzel, EA;Mendell, JT
通讯作者：
Mendell, JT
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko