Haemochromatosis is an iron-overload disorder with age-dependent oxidative stress and dysfunction in a variety of tissues. Mutations in HFE (histocompatability leucocyte antigen class I-like protein involved in iron homoeostasis) are responsible for most cases of haemochromatosis. We demonstrated recently that HFE is expressed exclusively in the basal membrane of RPE (retinal pigment epithelium). In the present study, we used Hfe−/− mice to examine ferritin levels (an indirect readout for iron levels) and morphological changes in retina. We found increased ferritin accumulation in retina in 18-month-old, but not in 2-month-old, mice with considerable morphological damage compared with age-matched controls. The retinal phenotype included hypertrophy and hyperplasia of RPE. RPE cells isolated from Hfe−/− mice exhibited a hyperproliferative phenotype. We also compared the gene expression profile between wild-type and Hfe−/− RPE cells by microarray analysis. These studies showed that many cell cycle-related genes were differentially regulated in Hfe−/− RPE cells. One of the genes up-regulated in Hfe−/− RPE cells was Slc7a11 (where Slc is solute carrier) which codes for the ‘transporter proper’ xCT in the heterodimeric cystine/glutamate exchanger (xCT/4F2hc). This transporter plays a critical role in cellular glutathione status and cell-cycle progression. We confirmed the microarrray data by monitoring xCT mRNA levels by RT (reverse transcription)–PCR and also by measuring transport function. We also found increased levels of glutathione and the transcription factor/cell-cycle promoter AP1 (activator protein 1) in Hfe−/− RPE cells. Wild-type mouse RPE cells and human RPE cell lines, when loaded with iron by exposure to ferric ammonium citrate, showed increased expression and activity of xCT, reproducing the biochemical phenotype observed with Hfe−/− RPE cells.
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Research Article|
November 11 2009
Absence of iron-regulatory protein Hfe results in hyperproliferation of retinal pigment epithelium: role of cystine/glutamate exchanger
Jaya P. Gnana-Prakasam;
Jaya P. Gnana-Prakasam
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
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Muthusamy Thangaraju;
Muthusamy Thangaraju
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
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Kebin Liu;
Kebin Liu
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
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Yonju Ha;
Yonju Ha
†Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, U.S.A.
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Pamela M. Martin;
Pamela M. Martin
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
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Sylvia B. Smith;
Sylvia B. Smith
†Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, U.S.A.
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Vadivel Ganapathy
Vadivel Ganapathy
1
*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, U.S.A.
1To whom correspondence should be addressed (email vganapat@mcg.edu).
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Publisher: Portland Press Ltd
Received:
March 12 2009
Revision Received:
August 06 2009
Accepted:
August 28 2009
Accepted Manuscript online:
August 28 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 424 (2): 243–252.
Article history
Received:
March 12 2009
Revision Received:
August 06 2009
Accepted:
August 28 2009
Accepted Manuscript online:
August 28 2009
Citation
Jaya P. Gnana-Prakasam, Muthusamy Thangaraju, Kebin Liu, Yonju Ha, Pamela M. Martin, Sylvia B. Smith, Vadivel Ganapathy; Absence of iron-regulatory protein Hfe results in hyperproliferation of retinal pigment epithelium: role of cystine/glutamate exchanger. Biochem J 1 December 2009; 424 (2): 243–252. doi: https://doi.org/10.1042/BJ20090424
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