Skip to main content
SpringerLink
Log in

Gadolinium-promoted cell cycle progression with enhanced S-phase entry via activation of both ERK and PI3K signaling pathways in NIH 3T3 cells

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

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

References

  1. Adding LC, Bannenberg GL, Gustafsson LE (2001) Cardiovasc Drug Rev 19:41–56

    PubMed  CAS  Google Scholar 

  2. Evans CH (1990) Biochemistry of the lanthanides. Plenum Press, New York

    Google Scholar 

  3. Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J (2005) J Comp Pathol 133:92–102

    Article  PubMed  CAS  Google Scholar 

  4. Mizgerd JP, Molina RM, Stearns RC, Brain JD, Warner AE (1996) J Leukoc Biol 59:189–195

    PubMed  CAS  Google Scholar 

  5. Iimuro Y, Yamamoto M, Kohno H, Itakura J, Fujii H, Matsumoto Y (1994) J Leukoc Biol 55:723–728

    PubMed  CAS  Google Scholar 

  6. Albaaj F, Hutchison AJ (2005) Expert Opin Pharmacother 6:319–328

    Article  PubMed  CAS  Google Scholar 

  7. Fricker SP (2006) Chem Soc Rev 35:524–533

    Article  PubMed  CAS  Google Scholar 

  8. Hashemy SI, Ungerstedt JS, Zahedi Avval F, Holmgren A (2006) J Biol Chem 281:10691–10697

    Article  PubMed  CAS  Google Scholar 

  9. Nicolosi AC, Strande JL, Hsu A, Fu X, Su J, Gross GJ, Baker JE (2008) J Mol Cell Cardiol 44:345–351

    Article  PubMed  CAS  Google Scholar 

  10. Nicolosi AC, Kwok CS, Logan B (2007) J Surg Res 139:286–291

    Article  PubMed  CAS  Google Scholar 

  11. Zeng T, Bett GC, Sachs F (2000) Am J Physiol Heart Circ Physiol 278:H548–H557

    PubMed  CAS  Google Scholar 

  12. Clemo HF, Stambler BS, Baumgarten CM (1998) Circ Res 83:147–157

    PubMed  CAS  Google Scholar 

  13. Clemo HF, Stambler BS, Baumgarten CM (1999) Circ Res 84:157–165

    PubMed  CAS  Google Scholar 

  14. Chang J, Wasser JS, Cornelussen RN, Knowlton AA (2001) Circulation 104:209–214

    Article  PubMed  CAS  Google Scholar 

  15. Bode F, Katchman A, Woosley RL, Franz MR (2000) Circulation 101:2200–2205

    PubMed  CAS  Google Scholar 

  16. Nicolosi AC, Kwok CS, Bosnjak ZJ (2004) J Heart Lung Transplant 23:1003–1007

    Article  PubMed  Google Scholar 

  17. Wang K, Li R, Cheng Y, Zhu B (1999) Coord Chem Rev 190–192:297–308

    Article  Google Scholar 

  18. Wang K, Cheng Y, Yang X, Li R (2003) Met Ions Biol Syst 40:707–751

    PubMed  CAS  Google Scholar 

  19. Thinnes FP, Hellmann KP, Hellmann T, Merker R, Schwarzer C, Walter G, Gotz H, Hilschmann N (2000) Mol Genet Metab 69:240–251

    Article  PubMed  CAS  Google Scholar 

  20. Thomsen HS (2004) Eur Radiol 14:1654–1656

    PubMed  Google Scholar 

  21. Abraham JL, Thakral C, Skov L, Rossen K, Marckmann P (2008) Br J Dermatol 158:273–280

    Article  PubMed  CAS  Google Scholar 

  22. Cowper SE, Rabach M, Girardi M (2008) Eur J Radiol 66:191–199

    Article  PubMed  Google Scholar 

  23. Rofsky NM, Sherry AD, Lenkinski RE (2008) Radiology 247:608–612

    Article  PubMed  Google Scholar 

  24. Bucala R (2008) J Am Coll Radiol 5:36–39

    Article  PubMed  Google Scholar 

  25. Chesney J, Bucala R (2000) Curr Rheumatol Rep 2:501–505

    Article  PubMed  CAS  Google Scholar 

  26. Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R (2004) Int J Biochem Cell Biol 36:598–606

    Article  PubMed  CAS  Google Scholar 

  27. Wang JF, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE (2007) Wound Repair Regen 15:113–121

    Article  PubMed  Google Scholar 

  28. Edward M, Quinn JA, Mukherjee S, Jensen MB, Jardine AG, Mark PB, Burden AD (2008) J Pathol 214:584–593

    Article  PubMed  CAS  Google Scholar 

  29. Spencer AJ, Wilson SA, Batchelor J, Reid A, Rees J, Harpur E (1997) Toxicol Pathol 25:245–255

    PubMed  CAS  Google Scholar 

  30. Behra-Miellet J, Gressier B, Brunet C, Dine T, Luyckx M, Cazin M, Cazin JC (1996) Methods Find Exp Clin Pharmacol 18:437–442

    PubMed  CAS  Google Scholar 

  31. Sieber MA, Lengsfeld P, Walter J, Schirmer H, Frenzel T, Siegmund F, Weinmann HJ, Pietsch H (2008) J Magn Reson Imaging 27:955–962

    Article  PubMed  Google Scholar 

  32. Sieber MA, Pietsch H (2008) Invest Radiol 43:338

    Article  Google Scholar 

  33. Sieber MA, Pietsch H, Walter J, Haider W, Frenzel T, Weinmann HJ (2008) Invest Radiol 43:65–75

    Article  PubMed  Google Scholar 

  34. Praeger FC, Gilchrest BA (1989) Proc Soc Exp Biol Med 190:28–34

    PubMed  CAS  Google Scholar 

  35. Smith JB, Smith L (1984) Biosci Rep 4:777–782

    Article  PubMed  CAS  Google Scholar 

  36. Yu S, Hu J, Yang X, Wang K, Qian ZM (2006) Biochemistry 45:11217–11225

    Article  PubMed  CAS  Google Scholar 

  37. Yu S, Yuan L, Yang X, Wang K, Ke Y, Qian ZM (2005) J Cell Biochem 94:508–519

    Article  PubMed  CAS  Google Scholar 

  38. Garcia Z, Kumar A, Marques M, Cortes I, Carrera AC (2006) EMBO J 25:655–661

    Article  PubMed  CAS  Google Scholar 

  39. Meloche S, Pouyssegur J (2007) Oncogene 26:3227–3239

    Article  PubMed  CAS  Google Scholar 

  40. Chambard JC, Lefloch R, Pouyssegur J, Lenormand P (2007) Biochim Biophys Acta 1773:1299–1310

    Article  PubMed  CAS  Google Scholar 

  41. Martinez-Gac L, Marques M, Garcia Z, Campanero MR, Carrera AC (2004) Mol Cell Biol 24:2181–2189

    Article  PubMed  CAS  Google Scholar 

  42. Kumar A, Marques M, Carrera AC (2006) Mol Cell Biol 26:9116–9125

    Article  PubMed  CAS  Google Scholar 

  43. Fu Y, Wang Q, Yang XG, Yang XD, Wang K (2008) J Biol Inorg Chem 13:1001–1009

    Article  PubMed  CAS  Google Scholar 

  44. Takahashi-Yanaga F, Sasaguri T (2008) Cell Signal 20:581–589

    Article  PubMed  CAS  Google Scholar 

  45. Bosco G, Du W, Orr-Weaver TL (2001) Nat Cell Biol 3:289–295

    Article  PubMed  CAS  Google Scholar 

  46. Roovers K, Assoian RK (2000) Bioessays 22:818–826

    Article  PubMed  CAS  Google Scholar 

  47. Harstad EB, Klaassen CD (2002) Toxicol Appl Pharmacol 180:178–185

    Article  PubMed  CAS  Google Scholar 

  48. Ishiyama H, Sato M, Matsumura K, Sento M, Ogino K, Hobara T (1995) Pharmacol Toxicol 77:293–298

    Article  PubMed  CAS  Google Scholar 

  49. Toker A (2008) Trends Biochem Sci 33:356–359

    Article  PubMed  CAS  Google Scholar 

  50. Hallstrom TC, Mori S, Nevins JR (2008) Cancer Cell 13:11–22

    Article  PubMed  CAS  Google Scholar 

  51. Dynlacht BD (2008) Cancer Cell 13:1–2

    Article  PubMed  CAS  Google Scholar 

  52. Ramos J, Sirisawad M, Miller R, Naumovski L (2006) Mol Cancer Ther 5:1176–1182

    Article  PubMed  CAS  Google Scholar 

  53. Aime S, Canavese C, Stratta P (2007) Kidney Int 72:1162–1163

    Article  PubMed  CAS  Google Scholar 

  54. Brambilla S, Valaperta S, Graziani G, Montanelli A (2008) Clin Biochem 41:1029–1033

    Article  PubMed  CAS  Google Scholar 

  55. De Broe ME (2008) Semin Dial 21:142–144

    Article  PubMed  Google Scholar 

  56. Tateyama M, Kubo Y (2006) Proc Natl Acad Sci USA 103:1124–1128

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by the National Natural Science Foundation of China (No. 20637010).

Author information

Authors and Affiliations

  1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, 100191, Beijing, People’s Republic of China

    Li-Juan Fu, Jin-Xia Li, Xiao-Gai Yang & Kui Wang

  2. National Research Laboratories of Natural and Biomimetic Drugs, Peking University Health Science Center, 100191, Beijing, People’s Republic of China

    Kui Wang

Authors
  1. Li-Juan Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Xia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Gai Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiao-Gai Yang or Kui Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-008-0442-z

Keywords

Search

Navigation