Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia.
Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia.
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DOI：
10.1016/j.jcmgh.2022.02.018
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发表时间：
2022
影响因子：
7.2
通讯作者：
Prochownik, Edward V.
中科院分区：
文献类型：
--
作者：
Wang, Huabo;Lu, Jie;Alencastro, Frances;Roberts, Alexander;Fiedor, Julia;Carroll, Patrick;Eisenman, Robert N.;Ranganathan, Sarangarajan;Torbenson, Michael;Duncan, Andrew W.;Prochownik, Edward V.
c-Myc（Myc）碱性螺旋-环-螺旋亮氨酸拉链（bHLH-ZIP）转录因子在大多数癌症中失调。与Max相关，Myc控制靶基因，这些靶基因监督代谢、核糖体生物合成、翻译和增殖。该Myc网络与Mlx网络交叉，Mlx网络由Myc样蛋白MondoA和ChREBP以及Max样Mlx组成。总之，这种扩展的Myc网络调节共同和不同的基因靶点。在这里，我们研究了Myc和/或Mlx消融在肝脏中的后果，特别是与肝细胞增殖、代谢和自发性肿瘤发生有关的后果。我们在I型酪氨酸血症的鼠模型中检查了缺乏Mlx（MlxKO）或Myc+Mlx（双KO [DKO]）的肝细胞在较长时间内重新填充肝脏的能力。我们还比较了这一点和其他相关的行为，表型，和转录组的肝脏与以前的特点MycKO，ChrebpKO，MycKO × ChrebpKO小鼠。随着扩展Myc网络的逐步拆除，肝细胞再生潜力恶化。MlxKO和DKO肝细胞中失调的基因和途径包括与翻译、线粒体功能和类似于非酒精性脂肪肝病的肝脂肪变性有关的基因和途径。Myc和Mlx网络显示出串扰，后者在靶基因调控中发挥不成比例的作用。所有队列均出现脂肪变性和早期脂肪性肝炎的分子证据。最后，MlxKO和DKO小鼠表现出广泛的肝腺瘤病。除了显示Myc和Mlx网络之间的合作外，这项研究还表明后者在维持增殖，代谢和翻译稳态方面更重要，同时作为良性肿瘤发生的抑制剂。GEO登录号：GSE 181371、GSE 130178和GSE 114634。
The c-Myc (Myc) Basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation, and proliferation. This Myc network crosstalks with the Mlx network, which consists of the Myc-like proteins MondoA and ChREBP, and Max-like Mlx. Together, this extended Myc network regulates both common and distinct gene targets. Here, we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism, and spontaneous tumorigenesis. We examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc+Mlx (double KO [DKO]) to repopulate the liver over an extended period of time in a murine model of type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes, and transcriptomes of the livers with those from previously characterized MycKO, ChrebpKO, and MycKO × ChrebpKO mice. Hepatocyte regenerative potential deteriorated as the Extended Myc Network was progressively dismantled. Genes and pathways dysregulated in MlxKO and DKO hepatocytes included those pertaining to translation, mitochondrial function, and hepatic steatosis resembling nonalcoholic fatty liver disease. The Myc and Mlx Networks were shown to crosstalk, with the latter playing a disproportionate role in target gene regulation. All cohorts also developed steatosis and molecular evidence of early steatohepatitis. Finally, MlxKO and DKO mice showed extensive hepatic adenomatosis. In addition to showing cooperation between the Myc and Mlx Networks, this study showed the latter to be more important in maintaining proliferative, metabolic, and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis. GEO accession numbers: GSE181371, GSE130178, and GSE114634.
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影响因子：
50.3
作者：
Carroll PA;Diolaiti D;McFerrin L;Gu H;Djukovic D;Du J;Cheng PF;Anderson S;Ulrich M;Hurley JB;Raftery D;Ayer DE;Eisenman RN
通讯作者：
Eisenman RN
影响因子：
3.7
作者：
Graves JA;Wang Y;Sims-Lucas S;Cherok E;Rothermund K;Branca MF;Elster J;Beer-Stolz D;Van Houten B;Vockley J;Prochownik EV
通讯作者：
Prochownik EV
DOI：
10.1038/gim.2017.101
发表时间：
2017-12-01
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Chinsky, Jeffrey M;Singh, Rani;Scott, C Ronald
通讯作者：
Scott, C Ronald
影响因子：
30.8
作者：
Bluteau, O;Jeannot, E;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
影响因子：
5.5
作者：
Camarda R;Williams J;Goga A
通讯作者：
Goga A