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Effects of RGMc on BMP2 and BMP6-mediated Gene Expression in Hep3B Liver Cells

ABSTRACT: Mutations in repulsive guidance molecule c (RGMc) / hemojuvelin (HJV) cause juvenile hemochromatosis, an aggravated iron overload disorder that presents early in life. Patients with juvenile hemochromatosis, and RGMc knockout mice, have diminished expression of the key iron-regulatory peptide, hepcidin. This suggests that RGMc plays a critical role in the regulation of iron homeostasis; however the mechanisms of RGMc actions are unknown. Recent studies have shown that RGMc directly binds to the growth factors, bone morphogenetic protein 2 and 6 (BMP2 and BMP6), and it is possible that this interaction regulates aspects of iron metabolism. We used microarrays to examine the effects of RGMc on BMP2- and BMP6-mediated gene expression. In our experimental model we treated Hep3B liver cells that had been serum starved for 16 hours as follows: (1) un-treated, (2) BMP2, (3) BMP2 + 10-fold molar excess of Noggin (a potent BMP2 inhibitor), (4) BMP2 + 20-fold molar excess of RGMc, (5) BMP6, (6) BMP6 + 10-fold molar excess of Noggin, (7) BMP6 + 20-fold molar excess of RGMc. Binding was allowed to proceed for BMP and Noggin or RGMc for 3 hr at 20°C prior to treatment of Hep3B cells. Treatment time was 4 hr at which cells were collected for RNA isolation.

ORGANISM(S): Homo sapiens  

SUBMITTER: Peter Rotwein  Mahta Nili 

PROVIDER: E-GEOD-20671 | ArrayExpress | 2010-06-23



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Soluble repulsive guidance molecule c/hemojuvelin is a broad spectrum bone morphogenetic protein (BMP) antagonist and inhibits both BMP2- and BMP6-mediated signaling and gene expression.

Nili Mahta M   Shinde Ujwal U   Rotwein Peter P  

The Journal of biological chemistry 20100608 32

Inactivating mutations in hemojuvelin/repulsive guidance molecule c (HJV/RGMc) cause juvenile hemochromatosis (JH), a rapidly progressive iron overload disorder in which expression of hepcidin, a key liver-derived iron-regulatory hormone, is severely diminished. Several growth factors in the bone morphogenetic protein (BMP) family, including BMP2 and BMP6, can stimulate production of hepcidin, a biological effect that may be modified by RGMc. Here we demonstrate that soluble RGMc proteins are po  ...[more]

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