探討FoxO1抑制肌肉生成的機制; Defining the mechanisms of FoxO1-mediated inhibition of myogenesis

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Title:	探討FoxO1抑制肌肉生成的機制;Defining the mechanisms of FoxO1-mediated inhibition of myogenesis
Authors:	方彥心;Yen-Hsin Fang
Contributors:	生命科學研究所
Keywords:	肌肉分化;myogenesis;differentiation;FoxO1;MRF family
Date:	2009-07-09
Issue Date:	2009-09-22 10:21:17 (UTC+8)
Publisher:	國立中央大學圖書館
Abstract:	肺泡型橫紋肌肉瘤為一好發於孩童時期的惡性腫瘤，其致病原因為在第二對染色體上的PAX3與第十三對染色體上的FoxO1形成一個基因異位的融合蛋白質PAX3-FoxO1，或較少發生的情形為: 第一對染色體上的PAX7與第十三對染色體上的FoxO1形成一個基因異位的融合蛋白質Pax7-FoxO1，此融合蛋白質有使正常細胞轉型成癌細胞的能力，並且會抑制肌肉的分化作用 ; 所以我們設想FoxO1對肌肉生成應扮演著重要的角色。近期的研究指出，當大量表現FoxO1會導致肌肉萎縮，且類型 I 的肌纖維數量會減少。為了更深入了解FoxO1於肌肉生成中的定位，我們探討當大量表現FoxO1時，對於C2C12肌肉細胞末期分化的影響，由我們的研究指出，FoxO1對於肌肉細胞末期分化為抑制效果。接下來，我們想找出是何條訊息傳遞路徑影響了這樣的抑制情形，哪一條訊息傳遞路徑可以回復由FoxO1所抑制的分化情形，很幸運的，我們找出insulin和LiCl可回復FoxO1抑制肌細胞分化的情形，並且這兩者的影響為一加成反應。除了這個發現，我們還找出了p38 這條訊息傳遞路徑可回復C2C12-FoxO1-H215R 肌纖維母細胞對 insulin導致肌肉細胞末期分化的效果。未來我們會著重於LiCl和Wnt-3a 對FoxO1在細胞的細胞核與細胞質轉移情形去研究。 Alveolar rhabdomyosarcoma is the most frequently detected malignant solid tumor in children and is associated with the translocated chimeric genes PAX3-, and Pax7- FoxO1. These chimeric proteins have potent transforming effects and are inhibitors of myogenic differentiation; thus it suggests that FoxO1 should play important roles in myogenesis. Recent studies have shown that over-expression of FoxO1 caused muscular atrophy and reduced type I fibers. To further elucidate the roles of FoxO1 in myogenesis, we examined the effects of FoxO1 over-expression on myogenic terminal differentiation, and we found that the effect was inhibitory. Subsequently, we like to identify the pathways mediating this effect to test whether they can rescue FoxO1 mediating inhibition of myogenesis. Luckly, we found that both insulin and LiCl could rescue FoxO1 inhibited myogenesis and their effects were synergistic. Another surprise was that we found p38 pathway can restore C2C12-FoxO1-H215R myoblasts insulin induced terminal differentiation. In the future, we will investigate whether LiCl and Wnt-3a treatment trigger the translocation of FoxO1 from nucleus.
Appears in Collections:	[Graduate Institute of Life Science] Electronic Thesis & Dissertation

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