Tuning cell cycle regulation with an iron key

Cell Cycle. 2007 Aug 15;6(16):1982-94. doi: 10.4161/cc.6.16.4603. Epub 2007 Jun 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin D1 / physiology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • Humans
  • Iron / antagonists & inhibitors
  • Iron / metabolism*
  • Iron Chelating Agents / pharmacology
  • Models, Biological
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology


  • Cyclin-Dependent Kinase Inhibitor p21
  • Iron Chelating Agents
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Iron