The role of Cdk4-Cyclin D1 complex in cell growth
Date Issued
2010
Date
2010
Author(s)
Chang, Chia-Chi
Abstract
Cell proliferation is driven by cell growth. During cell growth, cells upregulate macromolecular synthesis and thereby increase in size and mass. In order to rapidly accumulate biomass, cells must engage in the metabolic reprogramming. Growth factors and nutrients activate various signal transduction pathways ,and finally upregulate PI3K/AKT/mTOR pathway signaling. During cell growth, mTORC1-4EBP pathway up-regulates c-Myc protein translation. C-Myc assists PI3K/AKT/mTOR pathway in promoting mitochondria metabolic reprogramming and Warburg effect. C-Myc also promotes mitochondria biogenesis through it effects on downstream targets. Hif-1α inhibits c-Myc function by various mechanisms. By the effect on metabolic reprogramming and mitochondria biogenesis, Hif-1α decreases cell growth activity. But Hif-1α expression also under mTORC1-4EBP pathway control, so Hif-1α must be degradated by PHD system during cell growth. PHD system can respond mitochondria’s status, and normal mitochondria activity can maintain PHD activity. During cell growth Hif-1α is continuously expressed and then degradated through PHD regulation. Cdk4/cyclinD1 complex is also the important molecular during cell growth, and cyclin D1 expression also under mTORC1-4EBP pathway control. In the past, the function of Cdk4/cyclinD1 complex mainly focuses on the role of G1-S transition. Cdk4/cyclinD1 complex promotes cell cycle progression via the well characterized Rb/E2F pathway. But some studies show that Cdk4-cyclinD1 complex induces cell transformation by promoting cell growth rather than Rb/E2F pathway. In Drosophila melanogaster, the function of Cdk4-cyclinD complex in promoting cell growth needs Hph(Drosophila PHD). This result shows that Cdk4/cyclinD1 complex might involves in c-Myc and Hif-1α interrelationship.
In human embryonic fibroblast WI38 cells, the Cdk4/cyclin D1 complex activity inhibitor, Fascaplysin induced cell cycle arrest. Fascaplysin induced Hif-1α accumulation, and not interfered c-Myc protein level. Hif-1α accumulation not by decreased the hydroxylation at Pro-564 of Hif-1α, but might through enhanced Hif-1α protein production. These observations show that Cdk4/cyclin D1 complex activity may involves in regulation of Hif-1α protein level. Normal Cdk4/cyclin D1 complex activity assists growth functions of c-Myc by preventing Hif-1α accumulation. We also found that Fascaplysin interfered with the protein levels of S6K and β-Tublin. These results suggest a mechanistic link between Cdk4/cyclin D1 complex activity and regulation of protein levels which involve in cell growth. Fascaplysin treatment increases eIF-2α phosphorylation. This result may decreases protein translation initiation activity, in addition of protein synthesis.
In this study, we explore the role of Cdk4/cyclin D1 complex activity during cell growth by using Cdk4/cyclin D1 complex activity inhibitor, Fascaplysin. These results show that Cdk4/cyclin D1 complex activity may have effects in metabolic reprogramming and mitocindria biogenesis through regulation of Hif-1α, and also involve in protein synthesis. Through these functions, Cdk4/cyclin D1 complex can promote cell growth progression.
Subjects
Cell growth
Metabolic reprogramming
Type
thesis
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