Abstract
The aim of this study was to investigate whether Gd is able to exert the proliferation-promoting effect and to explore its possible underlying mechanism. We showed that Gd promoted cell cycle progression with increased S-phase entry in a concentration- and time-dependent manner in NIH 3T3 cells. The effect was further evidenced by the expressions of key proteins in driving cells through the G1/S transition point of the cell cycle. In the presence of Gd, the protein levels of cyclins D, E, and A were dramatically increased and demonstrated a characteristically temporal pattern of sequential mitotic events. Additionally, the levels of phosphorylated retinoblastoma protein were also significantly increased at certain time periods. To further elucidate the underlying mechanism, extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways were assessed. Both pathways were activated by Gd. Moreover, the levels of cyclin D and cyclin A were evaluated after the addition of the pharmacological inhibitors at early and late G1 phases, correspondingly, to reveal the contribution of the two pathways in the Gd-promoted G1/S transition. It showed that both pathways were needed for Gd-promoted cell cycle progression. The results presented here provide novel evidence to advance knowledge leading to further understanding of the mechanisms of both cell growth and death caused by Gd and may be helpful for more rational application of Gd-based compounds in the future.
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Abbreviations
- BrdU:
-
5-Bromo-2′-deoxyuridine
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- DMSO:
-
Dimethyl sulfoxide
- ERK:
-
Extracellular signal-regulated kinase
- FBS:
-
Fetal bovine serum
- MAPK:
-
Mitogen-activated protein kinase
- MEK:
-
Mitogen-activated protein kinase kinase
- MGd:
-
Gadolinium texaphyrin complex
- MTT:
-
3-(4,5-Dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide
- NSF:
-
Nephrogenic systemic fibrosis
- PBS:
-
Phosphate-buffered saline
- PI3K:
-
Phosphatidylinositol 3-kinase
- pRb:
-
Retinoblastoma tumor-suppressor protein
- Tris:
-
Tris(hydroxymethyl)aminomethane
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Acknowledgment
This work was supported by the National Natural Science Foundation of China (No. 20637010).
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Fu, LJ., Li, JX., Yang, XG. et al. Gadolinium-promoted cell cycle progression with enhanced S-phase entry via activation of both ERK and PI3K signaling pathways in NIH 3T3 cells. J Biol Inorg Chem 14, 219–227 (2009). https://doi.org/10.1007/s00775-008-0442-z
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DOI: https://doi.org/10.1007/s00775-008-0442-z