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研究生： 陳庭歡
Chen, Ting-Huan
論文名稱： YAP在肌肉細胞內調控其增生和分化
YAP as a molecular regulator of proliferation and differentiation in C2C12 myoblast
指導教授： 褚志斌
Chuu, Chih-Pin
汪宏達
Wang, Horng-Dar
口試委員: 張中和
Chang, Chung-Ho
夏興國
Shiah, Shine-Gwo
陳雅雯
Chen, Ya-Wen
學位類別： 博士
Doctor
系所名稱： 生命科學暨醫學院 - 生物科技研究所
Biotechnology
論文出版年： 2017
畢業學年度： 105
語文別： 英文
論文頁數： 82
中文關鍵詞： 肌肉前驅細胞 、分化 、增生
外文關鍵詞： YAP, C2C12, myogenesis
相關次數： 點閱：79  下載：0 
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    • Hippo訊息傳導途徑中的效應物YAP是癌症和正常發育中細胞增殖和分化的有力調節劑。已有研究證明YAP會促進衛星細胞和衛星細胞衍生的成肌細胞的增殖。然而目前對於YAP對肌肉細胞增生以及分化的調控還不清楚。我們使用過度表達或缺乏YAP的C2C12肌細胞來探討這個問題。我們的研究結果指出，YAP的過度表達增加了C2C12肌肉前驅細胞的增殖，而缺乏YAP會通過誘導發生G0 / G1細胞週期的阻滯來降低C2C12肌肉前驅細胞的生長。 YAP的過度表達增加了Ser 675上的beta-catenin的磷酸化程度，-catenin進核的量和TCF-4的轉錄活性，而減少YAP的表現則會降低它們。有趣的是 PKG-1抑製劑KT5823降低了Ser675上beta-catenin的磷酸化程度，TCf-4轉錄活性和減少C2C12肌肉前驅細胞增殖。 PKG-1是由cGMP活化而細胞內的cGMP可從 soluble guanylate and membrane-bound guanylate cyclase所產生。利用qPCR分析顯示，過度表達或降低YAP的表現並沒有改變GC-A（ANP的受體）的表現量。有趣的是，YAP增加了GC-B（CNP的受體）的表現量，以及在CNP的刺激下增加cGMP產生的量。另外，YAP的降低降低了GC-B，PKG-1，beta-catenin和TCF-4的蛋白表現量以及降低CNP刺激的cGMP產生的量。這些結果指出YAP通過GC-B-cGMP-PKG-1-beta-catenin/TCF-4的傳導路徑來調控C2C12肌肉前驅細胞的細胞增殖。
    MEK5 / ERK5 MAPK途徑對於早期肌肉細胞分化過程至關重要。我們發現在C2C12-YAP細胞中ERK5和MEK5被活化。 C2C12-YAP的細胞也比對照組細胞分化較多的肌管 (myotube)，並且表達較多調節肌肉細胞分化的轉錄因子。西方墨點分析顯示，C2C12-YAP細胞中Src和c-Abl被活化，c-Abl或Src抑制劑抑制了MEK5和ERK5的活化和C2C12肌肉前驅細胞的分化。通過共免疫沉澱實驗說明了YAP和ERK5途徑中的蛋白質之間的特異性相互作用，例如MEK激酶3（MEKK3）和ERK5。 MEKK3含有可與YAP相互作用的PPGY序列（aa 178-181）。定點突變實驗證明MEKK3 Y181F突變體的表達抑制MEK5 / ERK5的活化和C2C12肌肉前驅細胞的分化。這些結果表明YAP通過激活Abl / Src / MEKK3 / MEK5 / ERK5訊息傳導的途徑來促進C2C12肌肉前驅細胞的分化。

    The Hippo pathway effector YAP is a potent regulator of cell proliferation and differentiation in cancer and normal development. It has been shown that YAP promotes the proliferation of satellite cells and satellite cell-derived myoblasts. However, the signaling pathway which links YAP to myoblast growth and the role of YAP in myogenic differentiation remains to be established. We investigated this issue using C2C12 myoblasts over-expressing or lacking YAP. Our results showed that over-expression of YAP increased proliferation of C2C12 myoblasts, whereas knock-down of YAP reduced growth of C2C12 myoblasts by inducing the G0/G1 arrest. Over-expression of YAP increased phosphorylation levels of beta-catenin on Ser 675, nuclear translocation of beta-catenin and TCF-4 transcription activity, whereas knock-down of YAP decreased them. Interestingly, KT5823, the PKG-1 inhibitor, decreased the phosphorylation of beta-catenin on Ser 675, the TCF-4 transcriptional activity and the growth of C2C12 myoblasts, suggesting that YAP promotes C2C12 myoblast proliferation by phosphorylating beta-catenin on Ser 675 via PKG-1. PKG-1 is activated by cGMP which is generated by both soluble guanylate and membrane-bound guanylate cyclase. Real-time PCR analyses revealed that over-expression or knocking down of YAP did not alter levels of soluble guanylate cyclase and membrane-bound guanylate cyclase GC-A (the receptor for atrial natriuretic peptide). Interestingly, over-expression of YAP up-regulated membrane-bound guanylate cyclase GC-B, the receptor for C-type natriuretic peptide (CNP), and increased CNP-stimulated cGMP formation. In contrast, knock-down of YAP reduced levels of GC-B, PKG-1, beta-catenin and TCF-4 levels and CNP-stimulated cGMP formation. These data indicate that YAP regulates myoblast proliferation via the GC-B-cGMP-PKG-1-beta-catenin/TCF-4 signaling pathway.
    The MEK5/ERK5 MAPK cascade is essential for the early step of myogenesis. We found that ERK5 and MEK5 were activated in C2C12-YAP cells compared with control C2C12 (C2C12-vector) cells. C2C12-YAP stable cells also differentiated into myotubes better than C2C12-vector cells, and expressed elevated levels of myogenin, a transcription factor that regulates myogenesis, as well as elevated levels of myosin heavy chain, a skeletal muscle marker. Western blot analysis revealed that Src and c-Abl (Abelson murine leukemia viral oncogene homolog 1) activation were enhanced in C2C12-YAP cells. Conversely, treatment of inhibitors of c-Abl, Src, or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts. Specific interactions between YAP and proteins in the ERK5 pathway, such as MEK kinase 3 (MEKK3) and ERK5, were illustrated by coimmunoprecipitation experiments. MEKK3 contains the PPGY motif (aa 178–181), which may interact with YAP. Site-directed mutagenesis experiments revealed that expression of MEKK3 Y181F mutant inhibited MEK5/ERK5 activation and myogenic differentiation. These results suggest that YAP promotes muscle differentiation by activating the Abl/Src/MEKK3/MEK5/ERK5 kinase cascade.

    Abstract………………………………………………………………………………..i 中文摘要…………………………………………………………………………. iii Chapter 1 Introduction………………………………………………………………..1 1.1 Myogenesis………………………………………………………………………..1 1.2 YAP and TAZ……………………………………………………………………...2 1.3 YAP and Proliferation……………………………………………………………..3 1.4-catenin and Proliferation………………………………………………………..4 1.5 cGMP/PKG and proliferation……………………………………………………..4 1.6 YAP in differentiation…………………………………………………………… 6 Aim……………………………………………………………………………………6 Chapter 2 Part.1 Materials and Methods..…………………………………………….7 2.1 Reagents and Chemicals…………………………………………………………..7 2.2 Expression constructs and Cell Culture………………………..………………….8 2.3 Generation of Stably-transfected C2C12/YAP Myoblasts………….…………….8 2.4 Western Blot Analysis and Immunoprecipitation…………………………………9 2.5 Generation of YAP Knock-down Cell Lines…………………………...………...10 2.6 Immunoflusecence Microscopy………………………………….………………11 2.7 Measurement of Myotube Diameter……………………………………………..11 2.8 Isolation of Nuclear and Cytoplasmic Fractions……………………………...…12 2.9 Statistical analysis……………………………………………………………..…12 Chapter 2 Part.2 Materials and Methods..……………………………………………13 2.10 Cell line,material………………………...……………………………………...13 2.11 Western Blot Analysis………………….….........................................................13 2.12 Lentivirus production and infection…………..………………………………..14 2.13 Stable transfection……………………………………………………………..15 2.14 Luciferase reporter assay……………………………………………………….16 2.15 Cell proliferation assay………………………………………………………….16 2.16 Cell cycle analysis.........................................................................................…...17 2.17 QPCR….………………………………………….…………………………….17 2.18 Cyclic GMP determination……………………………………..……………….18 Chapter 3 Results Part1: YAP promotes myogenic differentiation via the MEK5-ERK5 pathway………………………………………………….……..……..19 3.1 YAP is required for myoblast differentiation……………………………………..19 3.2 YAP controls myogenic differentiation through activation of the MEK5/ERK5 pathway…………………………………………………………………………..…..20 3.3 YAP accumulates in the cytoplasm during myogenic differentiation……………21 3.4 YAP activates c-Abl and Src, upstream kinases of the MEKK3-MEK5-ERK5 pathway…………………………………………………………………………..…..21 3.5 TAZ promotes myogenic differentiation via ERK5/MEK5 signaling pathway…23 3.6 Discussion: YAP promotes myogenic differentiation via the MEK5-ERK5 pathway………………………………………………………………………………24 Part 2: YAP regulates the proliferation of C2C12 myoblasts via the membrane-bound guanylate cyclase GC-B- cGMP-PKG1--catenin signaling pathway……………..28 3.7 Alteration of YAP levels affects proliferation of C2C12 myoblasts……………28 3.8 Knock-down of YAP induces the G0/G1 arrest but not apoptosis in C2C12 myoblasts…………………………………………………………………..……….29 3.9 The instability of β-catenin caused by decreased p-β-catenin levels contributes to YAP knockdown-mediated inhibition of proliferation………………………….….30 3.10 YAP activates -catenin via the cGMP/PKG-1 signaling pathway………..…..31 3.11 YAP regulates the cGMP-PKG-1 signaling via membrane-bound guanylate cyclase GC-B, the receptor for C-natriuretic peptide (CNP)……………………….32 3.12 Discussion: YAP regulates the proliferation of C2C12 myoblasts via the membrane-bound guanylate cyclase GC-B- cGMP-PKG1--catenin signaling pathway………………………………………………………………………..……33 Chapter 4 Figures and figure legends……………………………………………38-62 Appendixes …………………………………………………………………….63-68 References…………………………………………………………………...…69-91

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