臺灣博碩士論文加值系統

生命的延續建築在細胞複製的忠實性(Fidelity)上，因此細胞對於細胞生長的機制勢必會有精密的調控。當細胞進行增生時會發生旺盛的代謝重組 (Metabolic reprogramming) ，包含Warburg effect和Glutamine-dependent anaplerosis兩種現象，並且透過PI3K/AKT/mTOR pathway。當細胞受到生長因子刺激時， mechanistics target of rapamycin complex 1 (mTORC1) 可以使Hypoxia induce factor-1α (HIF-1α) 和c-Myc大量表現，進而促進代謝重組。在果蠅的研究中指出，CDK4-cyclin D complex會透過 Prolyl hydroxylase (PHD) 系統影響細胞生長，另外的研究指出，PHD3會對Pyruvate kinase M2 isoform (PKM2) 進行hydroxylation，使得PKM2 recruit HIF-1α到Hypoxia response elements (HREs) 上，表現更多的PKM2和PHD3，對此路徑形成正迴饋的訊號放大。本實驗對HeLa細胞處理CDK4-cyclin D complex活性抑制劑Fascaplysin來探討CDK4-cyclin D complex對於細胞生長之調控，結果顯示CDK4-cyclin D complex除了導致c-Myc表現量上升外，還透過轉譯調控來促進PHD3、HIF-1α的蛋白質表現量。 c-Myc表現量上升能使得Anaplerosis大量活化，導致mTORC1能夠維持活性，同時造成抑制mTORC2的活性，PHD3和HIF-1α的表現量上升可能去促進PKM2的hydroxylation和對於HREs目標基因的表現，形成一正迴饋迴路放大PHD3和PKM2，進而促進代謝重組而影響細胞生長。

The mechanism of cell growth is strictly regulated.Two phenomena of metabolic reprogramming are involved in cell growth, including Warburg effect and Glutamine-dependent anaplerosis, which are regulated by PI3K/AKT/mTOR pathway. Under growth factors stimulation, cellular protein levels of Hypoxia induce factor-1α (HIF-1α) and c-Myc are massively increased by mechanistics target of rapamycin complex 1 (mTORC1). Our data show that CDK4-cyclin D complex increases protein level of c-Myc. Furthermore, our results demonstrate that increased c-Myc causes activation of anaplerosis that sustains the activity of mTORC1 but not that of mTORC2. In Drosophila studies, it has been shown that the promotion of cell growth by CDK4-cyclin D complex is mediated through Prolyl hydroxylase (PHD). A recent study demonstrated that hydroxylation of Pyruvate kinase M2 isoform (PKM2) by PHD3 enhances recruitment of HIF-1α to hypoxia response elements (HREs) and results in increased expression of PKM2 and PHD3. Consistently, our study shows that treatment with Fascaplysin, the inhibitor of CDK4-cyclin D complex, decreases the protein level of PHD3 in HeLa cell. It appears that PHD3 is involved in the hydroxylation of PKM2, which leads to the positive feedback to protein level of PHD3 and promotes metabolic reprogramming in cell growth.

致謝 i
中文摘要 ii
英文摘要 iii
目錄 iv
圖目錄 vi
引言 1
細胞生長是細胞進行自我複製的基礎 1
細胞生長需要代謝重組(Metabolic reprogram) 2
Warburg effect 2
Glutamine-dependent anaplerosis and cataplerosis 4
細胞生長中心調節路徑 PI3K/AKT/mTOR pathway 5
PI3K/AKT/mTOR pathway對Metabolic reprogram之調控 6
c-Myc對細胞生長的正迴饋調控 7
HIF-1α與c-Myc共同調控細胞生長 8
PHD2影響HIF-1α蛋白質含量 9
PHD3影響PKM2和HIF-1α交互作用促進Warburg effect 10
CDK4-cyclinD complex促細胞生長 11
材料與方法 15
細胞培養 15
細胞內涵物萃取 16
蛋白質濃度測定 17
蛋白質電泳與西方轉漬法 17
流式細胞儀細胞週期分析 18
結果 20
抑制Mitotic spindle形成使得細胞週期停滯 20
抑制CDK4-Cyclin D complex活性造成細胞週期延遲 20
抑制CDK4-Cyclin D comple活性造成HIF-1α 蛋白質含量減少 21
抑制CDK4-Cyclin D comple活性造成PHD2蛋白質含量減少 22
抑制26S proteosome活性造成HIF-1α蛋白質含量增加 22
抑制CDK4-Cyclin D complex活性造成c-Myc蛋白質含量減少 23
抑制CDK4-Cyclin D complex活性造成PHD3蛋白質含量減少 23
抑制26S proteosome活性造成PHD3蛋白質量增加 24
抑制CDK4-Cyclin D complex活性造成mTORCs活性變化 24
討論 26
CDK4-Cyclin D complex活性對於細胞週期的影響 26
CDK4-Cyclin D complex促使HIF-1α蛋白質含量上升 26
CDK4-Cyclin D complex透過c-Myc調控細胞生長 27
CDK4-Cyclin D complex透過PHD3蛋白質促使代謝重組發生 28
CDK4-Cyclin D complex影響PI3K/AKT/mTOR pathway 29
結果圖 31
參考文獻 40

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