通过AGO2的酸化,EGFR调节微RNA成熟,以应对低氧
Jia Shen1, Weiya Xia, Yekaterina B Khotskaya
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Nature
|May 3, 2013
概括
皮表皮生长因子受体 (EGFR) 通过酸化阿尔戈纳特2 (AGO2) 在缺氧期间抑制microRNA (miRNA) 成熟. 这种EGFR-AGO2相互作用影响瘤细胞存活率和侵入性,提供了潜在的临床见解.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 细胞应激反应的应激反应
背景情况:
- 微RNAs (miRNAs) 是基因表达的关键转录后调节者,其放松调节与癌症有关.
- 细胞压力,如缺氧,在固体瘤中很常见,但在压力下miRNA生物发生的上游调节者仍然不清楚.
- 了解瘤在压力期间如何控制miRNA表达对于癌症治疗至关重要.
研究的目的:
- 研究表皮生长因子受体 (EGFR) 在低氧压力下调节miRNA成熟的作用.
- 阐明EGFR影响miRNA生物发生的分子机制及其对瘤进展的影响.
- 为了确定在癌症中调节miRNA生物发生的潜在治疗点.
主要方法:
- 在低氧条件下研究了EGFR和阿尔戈纳特2 (AGO2) 之间的相互作用.
- 评估了EGFR介导的AGO2化 (Tyr 393) 对Dicer结合和miRNA处理的影响.
- 分析了前体miRNA长环结构在调节miRNA成熟中的作用.
- 与乳腺癌患者生存数据相关的AGO2酸化水平.
主要成果:
- 在低氧条件下,EGFR通过Tyr 393.3的AGO2酸化抑制了特定的瘤抑制剂类miRNA成熟.
- 缺氧增强了EGFR-AGO2的关联,增加了AGO2-Y393的酸化,并抑制了miRNA处理.
- 前体miRNA中的长环结构对于酸Y393-AGO2介导的miRNA成熟至关重要.
- 通过EGFR介导的AGO2化促进细胞在缺氧下生存和侵入性,与乳腺癌生存率较差相关.
结论:
- EGFR在通过AGO2.2的翻译后修改来调节miRNA成熟方面发挥着新的作用.
- 通过EGFR介导的miRNA生物发生抑制是瘤细胞适应和在低氧压力下生存的关键机制.
- 向EGFR-AGO2通路可能为癌症治疗提供新的治疗策略.
相关概念视频
Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA ends...
MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA ends...
mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a rapamycin-insensitive companion...

