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. 2002 May 1;363(Pt 3):431–436. doi: 10.1042/0264-6021:3630431

Ferritin expression modulates cell cycle dynamics and cell responsiveness to H-ras-induced growth via expansion of the labile iron pool.

Or Kakhlon 1, Yosef Gruenbaum 1, Z Ioav Cabantchik 1
PMCID: PMC1222495  PMID: 11964143

Abstract

Repression or overexpression of ferritin accelerated or retarded cell cycling respectively, via changes in the cellular labile iron pool (LIP). A rise in LIP is caused by ferritin repression enhanced growth, induced by H-ras, and reverted growth arrest is induced by dominant negative H-ras. The studies indicate that repression of ferritin expression provides a mechanism by which certain oncogenes lead to cell growth stimulation.

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Selected References

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  1. Bevilacqua M. A., Faniello M. C., Russo T., Cimino F., Costanzo F. P/CAF/p300 complex binds the promoter for the heavy subunit of ferritin and contributes to its tissue-specific expression. Biochem J. 1998 Nov 1;335(Pt 3):521–525. doi: 10.1042/bj3350521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chang H. C., Lee T. H., Chuang L. Y., Yen M. H., Hung W. C. Inhibitory effect of mimosine on proliferation of human lung cancer cells is mediated by multiple mechanisms. Cancer Lett. 1999 Oct 18;145(1-2):1–8. doi: 10.1016/s0304-3835(99)00209-8. [DOI] [PubMed] [Google Scholar]
  3. Cooper C. E., Lynagh G. R., Hoyes K. P., Hider R. C., Cammack R., Porter J. B. The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J Biol Chem. 1996 Aug 23;271(34):20291–20299. doi: 10.1074/jbc.271.34.20291. [DOI] [PubMed] [Google Scholar]
  4. Cozzi A., Corsi B., Levi S., Santambrogio P., Albertini A., Arosio P. Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase activity. J Biol Chem. 2000 Aug 18;275(33):25122–25129. doi: 10.1074/jbc.M003797200. [DOI] [PubMed] [Google Scholar]
  5. Epsztejn S., Kakhlon O., Glickstein H., Breuer W., Cabantchik I. Fluorescence analysis of the labile iron pool of mammalian cells. Anal Biochem. 1997 May 15;248(1):31–40. doi: 10.1006/abio.1997.2126. [DOI] [PubMed] [Google Scholar]
  6. Eriksson S., Gräslund A., Skog S., Thelander L., Tribukait B. Cell cycle-dependent regulation of mammalian ribonucleotide reductase. The S phase-correlated increase in subunit M2 is regulated by de novo protein synthesis. J Biol Chem. 1984 Oct 10;259(19):11695–11700. [PubMed] [Google Scholar]
  7. Gao J., Richardson D. R. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycle progression. Blood. 2001 Aug 1;98(3):842–850. doi: 10.1182/blood.v98.3.842. [DOI] [PubMed] [Google Scholar]
  8. Haneline L. S., Gobbett T. A., Ramani R., Carreau M., Buchwald M., Yoder M. C., Clapp D. W. Loss of FancC function results in decreased hematopoietic stem cell repopulating ability. Blood. 1999 Jul 1;94(1):1–8. [PubMed] [Google Scholar]
  9. Howe P. H., Dobrowolski S. F., Reddy K. B., Stacey D. W. Release from G1 growth arrest by transforming growth factor beta 1 requires cellular ras activity. J Biol Chem. 1993 Oct 5;268(28):21448–21452. [PubMed] [Google Scholar]
  10. Irani K., Xia Y., Zweier J. L., Sollott S. J., Der C. J., Fearon E. R., Sundaresan M., Finkel T., Goldschmidt-Clermont P. J. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science. 1997 Mar 14;275(5306):1649–1652. doi: 10.1126/science.275.5306.1649. [DOI] [PubMed] [Google Scholar]
  11. Kakhlon O., Gruenbaum Y., Cabantchik Z. I. Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells. Blood. 2001 May 1;97(9):2863–2871. doi: 10.1182/blood.v97.9.2863. [DOI] [PubMed] [Google Scholar]
  12. Keller H., Schu B., Rüdel R., Brinkmeier H. Cellular uptake and efficacy of antisense oligonucleotides against RNAs of two Na(+) channel isoforms. J Pharmacol Exp Ther. 2000 Oct;295(1):367–372. [PubMed] [Google Scholar]
  13. Kulp K. S., Green S. L., Vulliet P. R. Iron deprivation inhibits cyclin-dependent kinase activity and decreases cyclin D/CDK4 protein levels in asynchronous MDA-MB-453 human breast cancer cells. Exp Cell Res. 1996 Nov 25;229(1):60–68. doi: 10.1006/excr.1996.0343. [DOI] [PubMed] [Google Scholar]
  14. Marbach I., Licht R., Frohnmeyer H., Engelberg D. Gcn2 mediates Gcn4 activation in response to glucose stimulation or UV radiation not via GCN4 translation. J Biol Chem. 2001 Feb 28;276(20):16944–16951. doi: 10.1074/jbc.M100383200. [DOI] [PubMed] [Google Scholar]
  15. Pahl P. M., Yan X. D., Hodges Y. K., Rosenthal E. A., Horwitz M. A., Horwitz L. D. An exochelin of Mycobacterium tuberculosis reversibly arrests growth of human vascular smooth muscle cells in vitro. J Biol Chem. 2000 Jun 9;275(23):17821–17826. doi: 10.1074/jbc.M909918199. [DOI] [PubMed] [Google Scholar]
  16. Picard V., Renaudie F., Porcher C., Hentze M. W., Grandchamp B., Beaumont C. Overexpression of the ferritin H subunit in cultured erythroid cells changes the intracellular iron distribution. Blood. 1996 Mar 1;87(5):2057–2064. [PubMed] [Google Scholar]
  17. Rao S., Lowe M., Herliczek T. W., Keyomarsi K. Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene. 1998 Nov 5;17(18):2393–2402. doi: 10.1038/sj.onc.1202322. [DOI] [PubMed] [Google Scholar]
  18. Rittling S. R., Woodworth R. C. The synthesis and turnover of ferritin in rat L-6 cells. Rates and response to iron, actinomycin D, and desferrioxamine. J Biol Chem. 1984 May 10;259(9):5561–5566. [PubMed] [Google Scholar]
  19. Stacey D. W., Feig L. A., Gibbs J. B. Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol Cell Biol. 1991 Aug;11(8):4053–4064. doi: 10.1128/mcb.11.8.4053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tong L. A., de Vos A. M., Milburn M. V., Kim S. H. Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. J Mol Biol. 1991 Feb 5;217(3):503–516. doi: 10.1016/0022-2836(91)90753-s. [DOI] [PubMed] [Google Scholar]
  21. Tsuji Y., Akebi N., Lam T. K., Nakabeppu Y., Torti S. V., Torti F. M. FER-1, an enhancer of the ferritin H gene and a target of E1A-mediated transcriptional repression. Mol Cell Biol. 1995 Sep;15(9):5152–5164. doi: 10.1128/mcb.15.9.5152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vaisman B., Meyron-Holtz E. G., Fibach E., Krichevsky A. M., Konijn A. M. Ferritin expression in maturing normal human erythroid precursors. Br J Haematol. 2000 Aug;110(2):394–401. doi: 10.1046/j.1365-2141.2000.02167.x. [DOI] [PubMed] [Google Scholar]
  23. Vaisman B., Santambrogio P., Arosio P., Fibach E., Konijn A. M. An ELISA for the H-subunit of human ferritin which employs a combination of rabbit poly- and mice monoclonal antibodies and an enzyme labeled anti-mouse-IgG. Clin Chem Lab Med. 1999 Feb;37(2):121–125. doi: 10.1515/CCLM.1999.022. [DOI] [PubMed] [Google Scholar]
  24. Wu K. J., Polack A., Dalla-Favera R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science. 1999 Jan 29;283(5402):676–679. doi: 10.1126/science.283.5402.676. [DOI] [PubMed] [Google Scholar]

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