UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis.
SFT, a stimulator of iron (Fe) transport, has been described as a transmembrane protein that facilitates the uptake of ferrous and ferric iron in mammalian cells. This study was initiated to investigate the 5' regulatory region of SFT and its role in the etiology of hereditary hemochromatosis. Sequence analyses of the putative 5' regulatory region revealed that the SFT cDNA sequence corresponds to intron 6/exon 7 of UbcH5A, a member of E2 ubiquitin-conjugating enzymes, which is involved in the iron-dependent ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Further mRNA expression studies using a sequence-specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay showed that UbcH5A is significantly up-regulated in the liver of iron-overloaded patients with hereditary hemochromatosis, as previously published for SFT. However, in vitro studies on HepG2 cells failed to demonstrate any significant UbcH5A regulation in response to iron loading or iron chelation. In conclusion, in vivo mRNA expression data previously obtained for SFT might be attributed to UbcH5A. The role of UbcH5A and the ubiquitination pathway in the etiology of hereditary hemochromatosis remains to be elucidated further.
Gehrke
Sven G
SG
Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.
Riedel
Hans-Dieter
HD
Herrmann
Thomas
T
Hadaschik
Boris
B
Bents
Karin
K
Veltkamp
Claudia
C
Stremmel
Wolfgang
W
D020121:5' Untranslated Regions; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D006432:Hemochromatosis / Q000150:complications / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D019190:Iron Overload / Q000209:etiology / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D008025:Ligases / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes
D020121:5' Untranslated Regions; D018076:DNA, Complementary; D007502:Iron Chelating Agents; D033862:Iron-Binding Proteins; D012333:RNA, Messenger; D025801:Ubiquitin; D007501:Iron; C097308:UBE2D1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases