CDK4-Cyclin D對於細胞生長調控機制之探討

Abstract

細胞生長(Cell growth)是推動細胞自我複製(Self-reproduction)的基礎，細胞自我複製最重要的原則就是要遵守忠實性(Fidelity)。細胞在生長時會進行代謝重整(metabolic reprogram)，growth factor會刺激PI3K/AKT/mTOR pathway，mTORC1將4E-BP磷酸化，同時促使c-Myc、HIF-1α和Cyclin D大量產生。 c-Myc促進代謝重整，形成一個促進細胞生長的正回饋迴路(positive feedback loop)。而HIF-1α則是透過在各個層面對c-Myc產生拮抗，形成抑制細胞生長的負回饋迴路(negative feedback loop)。在一般的細胞生長情況下prolyl hydroxylase domain(PHD)系統會使得HIF-1α不斷的被分解，消除HIF-1α的負回饋迴路。在果蠅的研究指出過量表現CDK4-Cyclin D complex能透過果蠅的PHD系統促進細胞生長，顯示在細胞生長時CDK4-Cyclin D complex可能會透過PHD系統調控c-Myc和HIF-1α之間的平衡。本研究透過處理CDK4-Cyclin D complex活性抑制物Fascaplysin探討CDK4-Cyclin D complex對於細胞生長的調控，結果顯示在HeLa細胞中CDK4-Cyclin D complex會透過PHD系統去調控c-Myc和HIF-1α之間的平衡，進而影響細胞生長的進行，顯示CDK4-Cyclin D complex在細胞生長時會透過影響細胞內的代謝重整以及蛋白質的生合成以促進細胞生長。

Cell growth is the basis of cell self-reproduction driving. The most important standard of cell self-reproduction is to confirm the fidelity. Cell metabolism condition will regrogram during cell growth (metabolic reprogram). The growth factor will stimulate PI3K/AKT/mTOR signaling pathway during cell growth. Production of c-Myc, HIF-1α and Cyclin D will increase after 4E-BP is phosphorylated by mTORC1. Metabolic reprogram is enhanced by c-Myc and it will form a positive feedback loop that stimulate cell growth. However, HIF-1α will antagonize most effect of c-Myc during cell growth and form a negative feedback loop that inhibit cell growth. The prolyl hydroxylase domain (PHD) system will lead to HIF-1α degradation and eliminate the negative feedback loop of HIF-1α during normal cell growth. The studies in Drosophila melanogaster show that overexpression of CDK4-Cyclin D complex can promote cell growth through PHD of Drosophila. It suggests that CDK4-Cyclin D complex may regulate the balance between c-Myc and HIF-1α through the PHD system to promote cell growth. In this study, we treat Fascaplysin to investigate the cell growth regulation mechanism of CDK4-Cyclin D complex. Our results suggest that CDK4-Cyclin D complex may regulate the balance between c-Myc and HIF-1α through the PHD system to promote cell growth in HeLa cell.