The Role of CDK4-CyclinD in Metabolic Reprogramming of Cell Growth
Date Issued
2014
Date
2014
Author(s)
Shang, Yo-Jen
Abstract
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.
Subjects
CDK4
cyclin D
Fascaplysin
PHD3
HIF-1α
c-Myc
Metabolic reprogramming
mTORC1
Type
thesis
File(s)![Thumbnail Image]()
Loading...
Name
ntu-103-R00b43027-1.pdf
Size
23.32 KB
Format
Adobe PDF
Checksum
(MD5):58ac1cd4e02ede9123d1d0af35923f9a