ヴァリンのtRNA濃度と可用性は,白血病における複合体Iの構成を調節する.
Palaniraja Thandapani1, Andreas Kloetgen2,3, Matthew T Witkowski2
1Department of Pathology and Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA. Palaniraja.Thandapani@nyulangone.org.
Nature
|December 23, 2021
まとめ
移転RNA (tRNA) のバイオゲネシスの放出は癌を助長する. 食事中のバリンを制限すると,ミトコンドリアのエネルギー生成を標的とし,T-ALLに対する新しい治療戦略を提供することで,白血病細胞の成長を妨げます.
科学分野:
- 分子生物学
- 癌 生物学
- 代謝経路
背景:
- 転移RNA (tRNA) の生殖抑制は癌の進行に関与している.
- 腫瘍形成におけるtRNA脱調の具体的なメカニズムと結果は不明である.
- T細胞急性リンパ性白血病 (T-ALL) は,特定の腫瘍発生経路に依存しています.
研究 の 目的:
- T-ALLの病原性におけるtRNA生殖の役割を調査する.
- tRNAの放出が白血病に寄与するメカニズムを特定する.
- T-ALLにおけるtRNA代謝を標的とした治療戦略を探求する.
主な方法:
- CRISPR-Cas9スクリーニングは,tRNA生殖に関与する遺伝子を特定します.
- ヴァリンtRNA合成酵素の発現とNOTCH1によるその調節の分析
- マウスモデルでの食事によるバリン制限を含むインビボ試験.
- ミトコンドリア複合体I組立と酸化リン酸化の評価
- ゲノム全体にわたるCRISPR-Cas9機能喪失のスクリーンは,様々なバリン条件下で行われます.
主要な成果:
- 変異したバリンtRNAバイオゲネシスはT-ALLにおけるミトコンドリアのバイオエネルギー性を高めます.
- NOTCH1はバリンアミノアシルtRNA合成酵素を調節し,腫瘍性プログラムとtRNA供給を結びつける.
- 食事中のバリン摂取制限は白血病の負担を軽減し,マウスの生存率を向上させる.
- ヴァリン制限はミトコンドリア複合体Iの構成と酸化リン酸化を阻害する.
- SLC7A5とBCL2の遺伝的または薬学的ターゲティングは,T-ALLの増殖を抑制するためにバリン制限と連携します.
結論:
- tRNAの放出はT-ALLの病原性における重要な適応である.
- tRNA生殖,特にバリン代謝をターゲットにすることで,潜在的な治療方法が提供されます.
- 食事による介入は 血の悪性腫瘍を治療する有望な戦略です
関連する概念動画
02:26tRNA Activation
20.4K
Aminoacyl-tRNA synthetases are present in both eukaryotes and bacteria. Though eukaryotes have 20 different aminoacyl-tRNA synthetases to couple to 20 amino acids, many bacteria do not have genes for all of these aminoacyl-tRNA synthetases. Despite this, they still use all 20 amino acids to synthesize their proteins. For instance, some bacteria do not have the gene encoding the enzyme that couples glutamine with its partner tRNA. In these organisms, one enzyme adds glutamic acid to all of the...
20.4K
01:31Translation
16.2K
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...
Translation Produces the Building Blocks of Life
Proteins are...
16.2K
01:46Electron Transport Chain: Complex I and II
15.3K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
15.3K
02:41Protein Complex Assembly
12.9K
Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types. Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
Many viruses self-assemble into a fully functional unit using the infected host cell to...
12.9K
01:48ATP Synthase: Mechanism
15.5K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
15.5K
01:18ATP Synthase: Structure
13.4K
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
13.4K