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Regulation of Angiogenesis and Blood Supply01:24

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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to...
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RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
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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...
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Gene therapy is a technique where a gene is inserted into a person’s cells to prevent or treat a serious disease. The added gene may be a healthy version of the gene that is mutated in the patient, or it could be a different gene that inactivates or compensates for the patient’s disease-causing gene. For example, in patients with severe combined immunodeficiency (SCID) due to a mutation in the gene for the enzyme adenosine deaminase, a functioning version of the gene can be...
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プログラムされたトランスレーション・リーススルーは,抗血管原性VEGF-Axを生成する.

Sandeepa M Eswarappa1, Alka A Potdar2, William J Koch1

  • 1Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Cell
|June 21, 2014
PubMed
まとめ

哺乳類の細胞は,プログラムされたトランスレーション・リーススルー (PTR) を使用して,血管内皮成長因子A (VEGFA) mRNAから新しいVEGF-Axタンパク質同型を作成します. この新発見のメカニズムは,ヒトの組織と疾患に重大な影響を及ぼすユニークな抗血管新生因子を明らかにしています.

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科学分野:

  • 分子生物学は分子生物学である.
  • 遺伝学 遺伝学とは
  • バイオケミストリー バイオケミストリー

背景:

  • トランスレーション・リーススルーは,より単純な生物のプロテオームを,ストップコドンを超えたトランスレーションを拡張することによって拡張します.
  • 血管内皮成長因子A (VEGF-A) は,血管新生の重要な調節因子である.

研究 の 目的:

  • 哺乳類の細胞におけるプログラムトランスレーション・リーススルー (PTR) を調査する.
  • PTRによって生成される新しいタンパク質同型体とその機能を特定する.

主な方法:

  • VEGFA mRNA 3' UTRのシス作用成分を分析した.
  • hnRNP A2/B1.1.を使用して,PTRに関与するRNA結合タンパク質の識別.
  • VEGF-Axの抗血管新生活性に対する機能的測定法.
  • 追加的なリーススルーターゲットを対象とした全ゲノム分析.

主要な成果:

  • VEGFA mRNAからVEGF-Axを生成する哺乳類内皮細胞におけるプログラムされたトランスレーションルードスルー (PTR) が発見されました.
  • VEGFA 3' UTR と hnRNP A2/B1 の cis 作用要素が,UGA ストップ コドンのセリン解読を指示する上で決定的に重要であると特定されました.
  • VEGF-Axは,VEGF-Aの血管新生性作用と対照的に,抗血管新生性の特性を示しています.
  • VEGF-Axはヒトの組織に発現するが,大腸腺がんでは枯渇している;AGO1とMTCH2は他の読み込み標的として特定された.

結論:

  • 脊椎動物における新しいタンパク質調節PTRメカニズムを明らかにした.
  • VEGF-Axは,ヒトの健康と病気における潜在的な役割を持つ新しい抗血管新生因子を表しています.
  • 哺乳類のシステムにおけるトランスレーション・リーススルーの新たな標的とレギュレータを特定した.