Schematic illustration showing multiple effects of Fe chelators on the expression of molecules involved in cell-cycle control.
Iron chelators deplete intracellular Fe pools that can lead to a number of effects. In SK-N-MC neuroepithelioma cells, these compounds act through a p53-independent pathway to markedly increase the levels ofWAF1 and GADD45 mRNAs. However, the mRNAs of these cell-cycle inhibitory molecules are not efficiently translated, leading to possible cell-cycle dysregulation. Iron chelation also markedly reduces the expression of cyclins D1, D2, and D3, each of which forms a complex with cyclin-dependent kinase 4 (cdk4). The cyclin D-cdk4 complex is involved in progression through the G1phase and the phosphorylation of the retinoblastoma susceptibility gene product (pRb). Phosphorylation of this latter molecule is required for it to release the E2F family of transcription factors critical for the transcription of genes essential for cell-cycle progression. Chelators also depress the expression of cdk2, which combines with cyclin E to further phosphorylate pRb that is essential for G1/S progression (see “Discussion” for further details).
