老化により,C/EBPalpha成長停止の経路を切り替えることで,肝臓の増殖能力が低下する

Polina Iakova¹, Samir S Awad, Nikolai A Timchenko

¹Huffington Center on Aging, Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.

Cell

|May 22, 2003

まとめ

老化により肝臓の再生が阻害され,重要なタンパク質であるC/EBPalphaが細胞の成長を制御する仕組みが変化します. 細胞分裂を直接停止するのではなく,遺伝子の転写を抑制し,肝臓を阻害します.

科学分野:

ヘパトロジーと再生医療
分子生物学と老化について

背景:

肝臓は,損傷または部分肝切除術後の驚くべき再生能力を有しています.
老いた動物では肝臓の再生が著しく低下し,その背後にあるメカニズムは不明のままである.
肝細胞の増殖は通常,肝臓特異のタンパク質C/EBPalphaによって調節され,これはサイクリン依存キナーゼ (cdks) を阻害する.

研究の目的:

年齢による肝臓再生能力の低下に起因する分子メカニズムを調査する.
肝臓再生の文脈で,C/EBPalphaの機能が老化とともにどのように変化するかを明らかにする.

主な方法:

若い動物と古い動物の肝細胞増殖におけるC/EBPalphaの役割の分析.
C/EBPalphaを含む年齢特有のタンパク質複合体の識別と特徴付け.
クロマチン免疫プレシピテーション測定は,c-myc. を含む遺伝子プロモーターへの複合体の結合を評価するための測定である.

主要な成果:

老化により,C/EBPalpha経路は,サイクリン依存キナーゼ (cdks) を抑制することから,E2F依存転写を抑制することへとシフトする.
E2F標的遺伝子プロモーターに結合する年齢特有のC/EBPalpha-Rb-E2F4複合体が特定されました.
この複合体は,部分肝切除術後の高齢肝臓におけるc-mycおよび他のE2F標的遺伝子の誘導を防ぐ.

結論:

cdk阻害からE2F抑制へのC/EBPalpha機能の年齢依存のスイッチは,肝臓の再生を損なう.
このスイッチは,増殖に必要な不可欠なE2F標的遺伝子を誘導することができないことにつながります.
この発見は,年齢に関連した肝臓の再生能力の喪失の分子メカニズムを示しています.

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