EGFR信号如何改变肠干细胞代谢并调控其生长与分裂?
创作:MD 审核:MD 2022年09月17日
  • 在果蝇肠干细胞(ISC)中激活EGFR信号可通过Cic及其靶基因Pnt和Ets21C调控ISC生长和分裂,该过程依赖MEK活性并可在细胞不分裂时发生;
  • ERK通路通过调控DNA复制等促进ISC增殖,并上调氧化磷酸化和三羧酸循环基因,改变中肠的脂肪酸生物合成等代谢过程;
  • EGFR信号对促进ISC线粒体生物发生和增殖必需的,该过程也发生在人RPE-1细胞系;
  • Pnt直接上调mtTFB2促进线粒体的生物发生和上调β氧化以增加线粒体膜电位,从而促进ISC的生长和增殖。
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MD
EGFR-RAS-ERK信号可以促进多种细胞类型的生长和增殖,其过度激活会导致癌症发生。目前对EGFR的上游在信号转导过程中有深入的研究,但对其下游效应分子的特性和功能的研究较少。Current Biology近期发表的一项研究报道了EGFR信号及其下游靶基因Pnt和Ets21C不仅可上调细胞周期基因,还可上调线粒体的生物发生和脂肪酸氧化等基因,揭示了EGFR信号如何改变干细胞的代谢以及如何激活细胞生长和分裂的新机制。
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Current Biology [IF:10.9]

EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation

EGFR信号通过促进线粒体的生物发生和β氧化过程激活肠干细胞

10.1016/j.cub.2022.07.003

2022-07-26, Article

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EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

First Authors:
Chenge Zhang,Yinhua Jin

Correspondence Authors:
Bruce A Edgar

All Authors:
Chenge Zhang,Yinhua Jin,Marco Marchetti,Mitchell R Lewis,Omar T Hammouda,Bruce A Edgar

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