Sign up for Table of Contents Alerts.
Email this page
Print this page
Review
Tuning Cell Cycle Regulation with an Iron Key
Yu Yu, Zaklina Kovacevic and Des R. Richardson
volume 6 | issue 16
15 August 2007Pages: 1982 - 1994
Subscribe to this journal for $129/year
Iron (Fe) is essential for cellular metabolism e.g., DNA synthesis and its depletion causes G1/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 G1/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, p27Kip1, cyclin D1 and cyclin-dependent kinase 2 (cdk2). Additionally, Fe-depletion up-regulates the mRNA levels of the cdk inhibitor, p21CIP1/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 p21CIP1/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.
Authors
Yu Yu
Iron Metabolism and Chelation Program; Department of Pathology; University of Sydney; Sydney, New South Wales, Australia
Zaklina Kovacevic
Iron Metabolism and Chelation Program; Department of Pathology; University of Sydney; Sydney, New South Wales, Australia
Des R. Richardson
Iron Metabolism and Chelation Program; Department of Pathology; University of Sydney; Sydney, New South Wales, Australia