转录因子 MYC 在许多人类癌症中过度表达，并且在肿瘤的发生和进展中具有重要的因果作用。相比之下，MYC表达降低的Myc/-杂合小鼠的寿命延长了10-20%，并且几种与年龄相关的疾病的发生率或进展降低。据报道，Myc 杂合子小鼠的 mTOR 和 IGF1 信号传导降低，这两种途径的活性降低与不同物种的长寿相关。鉴于 MYC 在这些途径中的下游作用，Myc 杂合子中 mTOR 和 IGF1 信号传导的下调表明该调节网络中存在反馈环。在本次通讯中，我们提供了进一步的证据，证明 Myc/- 杂合子小鼠中 Myc 表达的减少会引起女性特异性循环 IGF1 的减少以及肝脏中 IGF1 蛋白的减少。特别是，Myc 表达减少导致靶向 Igf1 转录本的 miRNA 上调，从而抑制其翻译并导致 IGF1 蛋白水平降低。使用Argonaute (AGO)-CLIP测序，我们发现女性Myc杂合子中let-7、miR-122和miR-29靶位点的Igf1转录物中AGO结合富集，但男性Myc杂合子中没有。小鼠培养物和体内原代肝细胞中肝脏特异性 miR-122 的上调导致 IGF1 蛋白显着下调，但 mRNA 没有显着下调。 IGF1 水平降低会通过有据可查的负反馈关系增加垂体中 GH 的产生。与此相一致的是，我们发现骨骼中的 IGF1 水平（其中 miR-122 不表达）没有变化，这与女性 Myc 杂合子中骨质疏松症发病率的降低一致，尽管循环 IGF1 降低了。版权所有 © 2023 Petrashen、Verdesca、Kreiling 和塞迪维。

The transcription factor MYC is overexpressed in many human cancers and has a significant causal role in tumor incidence and progression. In contrast, Myc +/- heterozygous mice, which have decreased MYC expression, exhibit a 10-20% increase in lifespan and a decreased incidence or progression of several age-related diseases. Myc heterozygous mice were also reported to have decreased mTOR and IGF1 signaling, two pathways whose reduced activity is associated with longevity in diverse species. Given MYC's downstream role in these pathways, the downregulation of mTOR and IGF1 signaling in Myc heterozygotes suggests the presence of feedback loops within this regulatory network. In this communication we provide further evidence that the reduction of Myc expression in Myc +/- heterozygous mice provokes a female-specific decrease in circulating IGF1 as well as a reduction of IGF1 protein in the liver. In particular, reduced Myc expression led to upregulation of miRNAs that target the Igf1 transcript, thereby inhibiting its translation and leading to decreased IGF1 protein levels. Using Argonaute (AGO)-CLIP-sequencing we found enrichment of AGO binding in the Igf1 transcript at the target sites of let-7, miR-122, and miR-29 in female, but not male Myc heterozygotes. Upregulation of the liver-specific miR-122 in primary hepatocytes in culture and in vivo in mice resulted in significant downregulation of IGF1 protein, but not mRNA. Reduced levels of IGF1 increased GH production in the pituitary through a well-documented negative-feedback relationship. In line with this, we found that IGF1 levels in bone (where miR-122 is not expressed) were unchanged, consistent with the decreased incidence of osteoporosis in female Myc heterozygotes, despite decreased circulating IGF1.Copyright © 2023 Petrashen, Verdesca, Kreiling and Sedivy.