The Caenorhabditis elegans Myc-Mondo/Mad complexes integrate diverse longevity signals.
The Caenorhabditis elegans Myc-Mondo/Mad complexes integrate diverse longevity signals.
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DOI：
10.1371/journal.pgen.1004278
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发表时间：
2014-04
期刊：
影响因子：
4.5
通讯作者：
Samuelson AV
中科院分区：
文献类型：
--
作者：
Johnson DW;Llop JR;Farrell SF;Yuan J;Stolzenburg LR;Samuelson AV
Myc家族转录因子调控多种生物过程，包括细胞周期、生长、增殖、代谢和凋亡。在秀丽隐杆线虫中，“Myc相互作用网络”由两个相反的异二聚体复合物组成，它们在转录控制中具有拮抗功能：Myc- mondo:Mlx转录激活复合物和Mad:Max转录抑制复合物。在秀丽隐杆线虫中，Mondo、Mlx、Mad和Max分别由mml-1、mxml -2、mml-1和mxml -1编码。本研究显示秀丽隐杆线虫Myc-Mondo和Mad复合体在控制寿命方面具有类似的拮抗作用。缺失mml-1或mml- 2会缩短秀丽隐杆线虫的寿命。相反，失去MML-1或mxml -1会延长寿命，这取决于MML-1: mxml -2。MML-1:MXL-2和MML-1: MXL-1复合物在胰岛素信号通路和饮食限制通路中都起作用。此外，胰岛素样/IGF-1信号（ILS）的减少或饮食限制会增加MML-1的积累，这与Myc家族成员作为代谢状态传感器的观点一致。此外，我们发现Myc家族成员受到不同机制的调节，这将允许从代谢状态的不同信号中综合控制基因表达。我们比较了modENCODE项目中基于chip测序数据的假定靶基因，发现ILS的主要效应子（DAF-16/FoxO）、DR （PHA-4/FoxA）和Myc家族（MDL-1/Mad/Mxd）在共同靶基因上的基因组DNA结合存在显著重叠，这表明代谢状态的不同信号汇聚在影响衰老的重叠转录程序上。与此相一致的是，在这些共同目标基因上存在过度富集，这些基因在寿命、应激反应和碳水化合物代谢中起作用。此外，我们发现Myc家族成员也参与应激反应和蛋白质稳态的维持。总的来说，这些发现表明Myc家族成员整合了代谢状态的多种信号，以协调重叠的代谢和细胞保护转录程序，决定衰老的进展。转录因子是调节基因表达的重要蛋白质，在大多数生物过程中起着重要作用。我们的研究结果首次证明了秀丽隐杆线虫中一个小家族的转录因子在衰老中的作用。重要的是，这些蛋白质在包括人类在内的高等生物中有近亲，它们影响新陈代谢、细胞复制，并与癌症的发展有关。此外，一个同源物的缺失也与威廉姆斯-伯伦综合征有关，这种疾病的部分特征是过早衰老的迹象。我们的数据表明，这些转录因子在胰岛素/IGF-1信号传导和饮食限制中起作用，这两个高度保守的途径将营养感知与寿命联系起来。综上所述，我们的发现为一个蛋白质家族提供了令人兴奋的新见解，该家族可能是将营养感知与寿命联系起来所必需的，并对改善人类健康具有重要意义。
The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the “Myc interaction network” consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging. Transcription factors are essential proteins that regulate the expression of genes and play an important role in most biological processes. The results of our study presented here demonstrate for the first time a role in aging for a small family of transcription factors in the nematode worm Caenorhabditis elegans. Importantly, these proteins have close relatives in higher organisms, including humans that influence metabolism, cell replication, and have been implicated in the development of cancer. Moreover, the loss of one homologue has also been implicated in Williams-Beuren syndrome, a disease characterized in part by signs of premature aging. Our data demonstrate that these transcription factors function within insulin/IGF-1 signaling and dietary restriction, two highly conserved pathways that link nutrient sensing to longevity. Taken together, our findings provide exciting new insight into a family of proteins that may be essential for linking nutrient sensing to longevity and have implications for the improvement of human healthspan.
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影响因子：
29
作者：
Greer, Elisabeth R.;Perez, Carissa L.;Van Gilst, Marc R.;Lee, Brian H.;Ashrafi, Kaveh
通讯作者：
Ashrafi, Kaveh
影响因子：
56.9
作者：
Garsin, DA;Villanueva, JM;Ausubel, FM
通讯作者：
Ausubel, FM
DOI：
10.1073/pnas.1002575107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Henis-Korenblit, Sivan;Zhang, Peichuan;Kenyon, Cynthia
通讯作者：
Kenyon, Cynthia
影响因子：
5.4
作者：
Fuchs S;Bundy JG;Davies SK;Viney JM;Swire JS;Leroi AM
通讯作者：
Leroi AM
影响因子：
7
作者：
Halaschek-Wiener, J;Khattra, JS;Riddle, DL
通讯作者：
Riddle, DL