Iron-saturated lactoferrin stimulates cell cycle progression through PI3K/Akt pathway

Shin Hee Lee, Chul Woong Pyo, Dae Hyun Hahm, Jiyoung Kim, Sang-Yun Choi

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20 Citations (Scopus)

Abstract

Iron binding lactoferrin (Lf) is involved in the control of cell cycle progression. However, the molecular basis underlying the effects of Lf on cell cycle control, as well as its target genes, remains incompletely understood. In this study, we have demonstrated that a relatively low level of ironsaturated Lf, Lf(Fe3+), can stimulate S phase cell cycle entry, and requires Akt activation in MCF-7 cells. Lf(Fe3+) immediately induced Akt phosphorylation at Ser473, which subsequently induced the phosphorylation of two G1-checkpoint Cdk inhibitors, p21Cip/WAF1 and p27kip1. The Lf(Fe3+)-induced phosphorylation of Cdk inhibitors impaired their nuclear import behavior, thereby inducing cell cycle progression. However, the treatment of cells with a PI3K inhibitor, LY294002, almost completely blocked Lf(Fe3+)-stimulated cell cycle progression. LY294002 treatment abrogated Lf(Fe3+)-induced Akt activation, and prevented the cytoplasmic localization of p27kip1. Higher levels of p21Cip/WAF1 were also detected in the cytoplasmic sub-cellular compartment as a measure of cellular response to Lf(Fe3+). Consequently, the degree of phosphorylation of retinoblastoma protein was enhanced in response to Lf(Fe3+). Therefore, we conclude that Lf(Fe3+), as a potential antagonist of Cdk inhibitors, can facilitate the functions of E2F during progression to S phase via the Akt signaling pathway.

Original languageEnglish
Pages (from-to)37-42
Number of pages6
JournalMolecules and Cells
Volume28
Issue number1
DOIs
Publication statusPublished - 2009 Jun 17

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Keywords

  • Akt
  • Cell cycle
  • Lactoferrin
  • p21Cip/WAF1
  • p27kip1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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