Tuning cell cycle regulation with an iron key.
Iron (Fe) is essential for cellular metabolism e.g., DNA synthesis and its depletion causes G(1)/S arrest and apoptosis. Considering this, Fe chelators have been shown to be effective anti-proliferative agents. In order to understand the anti-tumor activity of Fe chelators, the mechanisms responsible for G(1)/S arrest and apoptosis after Fe-depletion have been investigated. These studies reveal a multitude of cell cycle control molecules are regulated by Fe. These include p53, p27(Kip1), cyclin D1 and cyclin-dependent kinase 2(cdk2). Additionally, Fe-depletion up-regulates the mRNA levels of the cdk inhibitor, p21(CIP1/WAF1), but paradoxically down-regulates its protein expression. This effect could contribute to the apoptosis observed after Fe-depletion. Iron-depletion also leads to proteasomal degradation of p21(CIP1/WAF1) and cyclin D1 via an ubiquitin-independent pathway. This is in contrast to the mechanism in Fe-replete cells, where it occurs by ubiquitin-dependent proteasomal degradation. Up-regulation of p38 mitogen-activated protein kinase (MAPK) after Fe-depletion suggests another facet of cell cycle regulation responsible for inhibition of proliferation and apoptosis induction. Elucidation of the complex effects of Fe-depletion on the expression of cell cycle control molecules remains at its infancy. However, these processes are important to dissect for complete understanding of Fe-deficiency and the development of chelators for cancer treatment.
Yu
Yu
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Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
Kovacevic
Zaklina
Z
Richardson
Des R
DR
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007501:Iron / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008954:Models, Biological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D007502:Iron Chelating Agents; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D007501:Iron