High Intrinsic Oncogenic Potential in the Myc-Box-Deficient Hydra Myc3 Protein.
High Intrinsic Oncogenic Potential in the Myc-Box-Deficient Hydra Myc3 Protein.
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作者：
原癌基因myc主要在脊椎动物细胞培养系统中被深入研究。Myc转录因子控制基本的细胞过程，例如细胞增殖、细胞周期控制和干细胞维持。Myc与Max蛋白相互作用，Myc/Max异二聚体调节数千个靶基因。淡水水螅的基因组编码四个myc基因（myc 1 -4）。先前的结构和生化表征表明，水螅Myc 1和Myc 2蛋白与脊椎动物c-Myc具有高度相似性，其表达模式表明在成体干细胞维持中具有功能。相比之下，另一种称为Myc 3的Hydra Myc蛋白是高度不同的，缺乏共同的N-末端结构域和所有保守的Myc盒。单细胞转录组分析显示，Myc 3基因在致力于神经和腺细胞分化的不同间质前体细胞群体中表达，其中Myc 3蛋白可能会抵消Myc 1和Myc 2的干性作用，从而允许实施分化程序。体外DNA结合研究表明，Myc 3与Hydra Max发生二聚化，并且该二聚体有效地结合含有典型Myc共有基序（E-box）的DNA。在禽成纤维细胞培养物中的体内细胞转化测定进一步揭示了与Hydra Myc 2或Myc 1相比，保守的Myc 3 C-末端中致癌转化的意外高潜力。Myc 3蛋白的结构建模预测其bHLH-LZ结构域中参与Myc 3/Max二聚化的保守氨基酸残基。突变人c-Myc（MYC）序列中的这些氨基酸残基导致其细胞转化潜力显著降低。我们在致癌转化和细胞分化的背景下讨论了我们的发现，这两个都与人类癌症有关，其中Myc是一个主要的驱动因素。
The proto-oncogene myc has been intensively studied primarily in vertebrate cell culture systems. Myc transcription factors control fundamental cellular processes such as cell proliferation, cell cycle control and stem cell maintenance. Myc interacts with the Max protein and Myc/Max heterodimers regulate thousands of target genes. The genome of the freshwater polyp Hydra encodes four myc genes (myc1-4). Previous structural and biochemical characterization showed that the Hydra Myc1 and Myc2 proteins share high similarities with vertebrate c-Myc, and their expression patterns suggested a function in adult stem cell maintenance. In contrast, an additional Hydra Myc protein termed Myc3 is highly divergent, lacking the common N-terminal domain and all conserved Myc-boxes. Single cell transcriptome analysis revealed that the myc3 gene is expressed in a distinct population of interstitial precursor cells committed to nerve- and gland-cell differentiation, where the Myc3 protein may counteract the stemness actions of Myc1 and Myc2 and thereby allow the implementation of a differentiation program. In vitro DNA binding studies showed that Myc3 dimerizes with Hydra Max, and this dimer efficiently binds to DNA containing the canonical Myc consensus motif (E-box). In vivo cell transformation assays in avian fibroblast cultures further revealed an unexpected high potential for oncogenic transformation in the conserved Myc3 C-terminus, as compared to Hydra Myc2 or Myc1. Structure modeling of the Myc3 protein predicted conserved amino acid residues in its bHLH-LZ domain engaged in Myc3/Max dimerization. Mutating these amino acid residues in the human c-Myc (MYC) sequence resulted in a significant decrease in its cell transformation potential. We discuss our findings in the context of oncogenic transformation and cell differentiation, both relevant for human cancer, where Myc represents a major driver.
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DOI：
10.1038/s41580-020-0215-2
发表时间：
2020-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baluapuri A;Wolf E;Eilers M
通讯作者：
Eilers M
Hydra基因组的染色体尺度表观遗传图揭示了细胞态的保守调节剂。
影响因子：
7
作者：
Cazet, Jack F.;Siebert, Stefan;Little, Hannah Morris;Bertemes, Philip;Primack, Abby S.;Ladurner, Peter;Achrainer, Matthias;Fredriksen, Mark T.;Moreland, R. Travis;Singh, Sumeeta;Zhang, Suiyuan;Wolfsberg, Tyra G.;Schnitzler, Christine E.;Baxevanis, Andreas D.;Simakov, Oleg;Hobmayer, Bert;Juliano, Celina E.
通讯作者：
Juliano, Celina E.
影响因子：
4.6
作者：
Castell A;Yan Q;Fawkner K;Hydbring P;Zhang F;Verschut V;Franco M;Zakaria SM;Bazzar W;Goodwin J;Zinzalla G;Larsson LG
通讯作者：
Larsson LG
影响因子：
5.4
作者：
Conacci-Sorrell, Maralice;McFerrin, Lisa;Eisenman, Robert N.
通讯作者：
Eisenman, Robert N.
影响因子：
16.6
作者：
Fagnocchi L;Cherubini A;Hatsuda H;Fasciani A;Mazzoleni S;Poli V;Berno V;Rossi RL;Reinbold R;Endele M;Schroeder T;Rocchigiani M;Szkarłat Ż;Oliviero S;Dalton S;Zippo A
通讯作者：
Zippo A