MyoD對於PGC-1α 基因表現之調控機制;The mechanism of PGC-1α gene expression regulated by MyoD

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Title:	MyoD對於PGC-1α 基因表現之調控機制;The mechanism of PGC-1α gene expression regulated by MyoD
Authors:	張如慧;Ju-Hui Chang
Contributors:	生命科學研究所
Keywords:	肌肉;MyoD;PGC-1
Date:	2005-03-28
Issue Date:	2009-09-22 10:18:08 (UTC+8)
Publisher:	國立中央大學圖書館
Abstract:	MRF (Myogenic Regulatory Factor)家族中basic Helix-Loop-Helix轉錄因子-MyoD、Myf-5、Myogenin以及MRF-4，為肌肉細胞品系的決定者，而它們也是調控肌肉細胞末期分化的主要因子。若將MRF家族的其中一員於非肌肉細胞中過度表現時，則會使得這些細胞轉變成肌肉細胞。然而肌肉細胞要轉變為成熟的肌肉細胞，則還須有MEF-2 (Myocyte Enhancer Factor-2)的參與。MEF-2和肌肉生成之bHLH蛋白會以形成異行雙聚物的方式去調控肌肉特化基因的表現進而促進肌肉細胞的成熟。而另一轉錄因子FKHR (Forkhead in Rhabdormyosarcoma)在肌肉末期分化上也扮演著相同的重要角色，它會促進肌纖維母細胞間的融合，此為肌肉細胞分化的必要過程。最近的研究指出，MEF-2和FKHR皆會調控PGC-1α (Peroxisome proliferator-activated receptor (PPAR)-γ Coactivator-1)的表現，而PGC-1α是調控慢收縮肌纖維形成的重要因子。既然MEF-2 和 FKHR 這這兩者都會影響肌肉之末期分化，因此引發我們進一步去研究，肌肉中是否有其他肌肉特有轉錄因子，例如MyoD或其同一家族的其他成員是否也會調控PGC-1α。本篇主要是針對肌肉細胞品系決定的調節者MyoD (myogenic determination factor) 進行研究。在本篇研究中，我們發現 PGC-1 α 核心驅動子上之兩個 E-box在MyoD之作用上扮演著極關鍵的角色。將這兩個E-box其中之一突變後，都會明顯減少經由MyoD 所誘發之PGC-1 α 核心驅動子之轉錄活性。此外，我們也發現當肌纖維母細胞分化成肌管(myotube)時，PGC-1α的表現也隨之增加。而根據我們以反轉錄病毒方法所製備之MyoD穩定表達細胞株也發現，當其分化成肌管時，PGC-1α的表現同樣也會隨之增加。因為 PGC-1α被認為是決定肌纖維種類之主要調控者，我們的結果顯示MyoD不僅是和肌肉品系的決定以及末期分化有關，它也可能會影響成熟肌肉細胞的肌纖維種類以及代謝方式的轉換。 Determination of myogenic lineage is dictated by the function of bHLH transcription factors of MRF (Myogenic Regulatory Factor) family, which consists of MyoD, Myogenin, Myf-5 and MRF-4, and they are also the major factors regulating terminal differentiation of muscle cells. Overexpression of any one of the MRF family in several non-myogenic cells can induce their trans-differentiation into myogenic lineage. However, myoblsts differentiate into mature muscle cells still need the help of MEF-2 (Myocyte Enhancer Factor-2). MEF-2 proteins can cooperate with myogenic bHLH proteins as a heterodimer to regulate the expression of muscle-specific genes and commit myoblasts to terminal differentiation. Another factor, FKHR, also plays a role in terminal differentiation by promoting the fusion of myoblasts which is the essential process of myoblasts differentiation. Recently, PGC-1α (Peroxisome proliferator-activated receptor PPAR-γ Coactivator-1α) was shown to promote the formation of slow-twitch fibers, and which is regulated by MEF2 and FKHR. Since MEF-2 and FKHR are both implicated in the terminal muscle differentiation, it prompts us to study the regulation of PGC-1α in muscle by other muscle-specific transcription factors, such as MyoD and its family members. Here we show that MyoD can activate PGC-1α expression by binding to two putative E-boxes localized to its core promoter. Mutation of either site significantly reduced MyoD mediated transactivation. We also found out that when myoblast differentiates into myotube the expression of PGC-1α is up-regulated. The expression of PGC-1α also increased in retrovirus-mediated MyoD-overexpressed cells when they differentiate into myotubes. Since PGC-1α is suggested to be the principle factor regulating muscle fiber type determination, our results indicate that MyoD is not only involved in the lineage determination and terminal differentiation, but may also implicated in the fiber-type and metabolic switch of mature muscle cells.
Appears in Collections:	[Graduate Institute of Life Science] Electronic Thesis & Dissertation

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