アンドロゲン受容体調節遺伝子活性化プログラムの lncRNA依存メカニズム
Liuqing Yang1,2, Chunru Lin1,2, Chunyu Jin1
1Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Nature
|August 16, 2013
まとめ
2つの長いノンコーディングRNAs (lncRNAs),PRNCR1とPCGEM1は,攻撃的な前立腺がんにおけるアンドロゲン受容体 (AR) の活性を増強する. これらのlncRNAをターゲットにすることで,腫瘍の成長が抑制され,それがカストレーション抵抗性の鍵であることを示唆しています.
科学分野:
- 分子生物学は分子生物学である.
- 腫瘍学 腫瘍学
- 遺伝学 遺伝学とは
背景:
- 細胞決定と組織ホメオスタシスにおける長い非コーディングRNA (lncRNAs) の役割は知られているが,遺伝子転写におけるその機能は不明である.
- アンドロゲン受容体 (AR) は前立腺がん細胞のアイデンティティと行動を調節し,ホルモン耐性がんではしばしばリガンド独立に作用する.
- PRNCR1とPCGEM1は,攻撃的な前立腺がんにおいて過剰に発現するlncRNAである.
研究 の 目的:
- 前立腺がんの進行におけるlncRNAs PRNCR1およびPCGEM1の役割を調査する.
- これらの lncRNA がアンドロゲン受容体とどのように相互作用するかを決定する.
- これらのIncRNAを対象に,カストレーション耐性前立腺がんの治療の可能性を調査する.
主な方法:
- PRNCR1とPCGEM1のアンドロゲン受容体への結合を調査した.
- ショートヘアピンRNA (shRNA) を利用して,これらのlncRNAをカストレーション耐性前立腺がん細胞系に標的とした.
- lncRNAターゲティングがAR媒介の遺伝子活性化,増殖,腫瘍異種移植の成長に与える影響を in vivoで評価した.
主要な成果:
- PRNCR1とPCGEM1は順番にアンドロゲン受容体と結合し,リガンド依存性およびリガンド独立性AR媒介遺伝子活性化および増殖の両方を強化します.
- PRNCR1がアセチル化されたARと結合し,DOT1LはPCGEM1がメチル化されたARに結合するために必要である.
- PCGEM1は,Pygopus 2 PHDドメインによるタンパク質マークの認識を通じて,エンハンサー・プロモーター・ループを容易にする.
- これらのlncRNAをshRNAで標的にすると,カストレーション耐性前立腺がんモデルにおける腫瘍異種移植の成長が著しく抑制される.
- これらのlncRNAは,抵抗性前立腺がん細胞における断絶されたARと全長ARの両方の活性化に必要である.
結論:
- 過剰発現したlncRNAs PRNCR1とPCGEM1は,攻撃性およびカストレーション抵抗性前立腺がんにおけるARシグナル伝達と増殖を強化する上で重要な役割を果たします.
- これらのlncRNAは,抵抗性前立腺がん細胞におけるリガンド独立AR活性化に不可欠である.
- PRNCR1とPCGEM1をターゲットにすることは,カストレーション耐性前立腺がんの潜在的な治療戦略を提供します.
関連する概念動画
02:39lncRNA - Long Non-coding RNAs
In humans, more than 80% of the genome gets transcribed. However, only around 2% of the genome codes for proteins. The remaining part produces non-coding RNAs which includes ribosomal RNAs, transfer RNAs, telomerase RNAs, and regulatory RNAs, among other types. A large number of regulatory non-coding RNAs have been classified into two groups depending upon their length – small non-coding RNAs, such as microRNA, which are less than 200 nucleotides in length, and long non-coding RNA (lncRNA)...
02:39lncRNA - Long Non-coding RNAs
In humans, more than 80% of the genome gets transcribed. However, only around 2% of the genome codes for proteins. The remaining part produces non-coding RNAs which includes ribosomal RNAs, transfer RNAs, telomerase RNAs, and regulatory RNAs, among other types. A large number of regulatory non-coding RNAs have been classified into two groups depending upon their length – small non-coding RNAs, such as microRNA, which are less than 200 nucleotides in length, and long non-coding RNA (lncRNA)...
02:36RNA Polymerase II Accessory Proteins
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
02:04Co-activators and Co-repressors
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
02:04Co-activators and Co-repressors
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
01:31Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes: