Iron-saturated lactoferrin stimulates cell cycle progression through PI3K/Akt pathway.
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(Fe(3+)), can stimulate S phase cell cycle entry, and requires Akt activation in MCF-7 cells. Lf(Fe(3+)) immediately induced Akt phosphorylation at Ser473, which subsequently induced the phosphorylation of two G1-checkpoint Cdk inhibitors, p21(Cip/WAF1) and p27(kip1). The Lf(Fe(3+))-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(Fe(3+))-stimulated cell cycle progression. LY294002 treatment abrogated Lf(Fe(3+))-induced Akt activation, and prevented the cytoplasmic localization of p27(kip1). Higher levels of p21(Cip/WAF1) were also detected in the cytoplasmic sub-cellular compartment as a measure of cellular response to Lf(Fe(3+)). Consequently, the degree of phosphorylation of retinoblastoma protein was enhanced in response to Lf(Fe(3+)). Therefore, we conclude that Lf(Fe(3+)), as a potential antagonist of Cdk inhibitors, can facilitate the functions of E2F during progression to S phase via the Akt signaling pathway.
Lee
Shin-Hee
SH
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Pyo
Chul-Woong
CW
Hahm
Dae Hyun
DH
Kim
Jiyoung
J
Choi
Sang-Yun
SY
D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007501:Iron / Q000737:chemistry; D007781:Lactoferrin / Q000737:chemistry / Q000494:pharmacology*; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D002867:Chromones; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D007781:Lactoferrin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein; D012694:Serine; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; C082171:lactoferricin B; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one