Disease relevance of Vnn1

• Vanin and co-workers (Kubrina et al., Biochim. Biophys. Acta 1176 (1993) 240-244; Mikoyan et al., Biochim. Biophys. Acta 1269 (1995) 19-24) reported that short term (30 min) iron (Fe) exposure potentiates nitric oxide (NO) production in tissues of septic shock mice, based on increased formation of NO complex by diethyldithiocarbamate (DETC) [1].

High impact information on Vnn1

• These data suggest that Vanin-1 regulates late adhesion steps of thymus homing under physiological, noninflammatory conditions [2].
• Transfection of thymic stromal cells with the Vanin-1 cDNA enhances thymocyte adhesion in vitro [2].
• An anti-Vanin-1 antibody blocks the binding of pro-T cells to thymic sections in vitro, the in vivo accumulation of bone marrow cells around cortical thymic vessels, and long-term thymic regeneration [2].
• Vnn3/Vnn1 map within a conserved haplotype block and show expression levels that are strictly cis-regulated by this haplotype [3].
• Vanin genes code for a pantetheinase involved in the production of cysteamine, a key regulator of host responses to inflammatory stimuli [3].

Biological context of Vnn1

• The three human Vanin genes map to the same region of Chromosome 6q [4].
• An ESTs description of the new Vanin gene family conserved from fly to human [4].
• Sexually dimorphic expression of protease nexin-1 and vanin-1 in the developing mouse gonad prior to overt differentiation suggests a role in mammalian sexual development [5].
• The absence of Vnn messenger RNA expression and lack of pantetheinase protein activity in tissues are associated with susceptibility to malaria and are linked to a complex rearrangement in the Vnn3 promoter region [3].
• Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress [6].

Anatomical context of Vnn1

• The mouse Vanin-1 molecule was recently identified and found to be involved in the colonization of the thymus by hematopoietic precursor cells [4].
• In the present study we investigate in detail the expression and regulation of Vanin-1 in the fetal testis [7].
• Our findings account for the sex- and cell-type-specific expression of Vanin-1 in the developing mouse gonad in vivo, which we suggest is required to provide an appropriate environment for male germ cell development [7].
• The expression of Vanin-1 was abolished in Leydig cells of a mouse mutant lacking SF-1 in that cell type [7].
• Migration of hematopoietic precursor cells to the thymus is shown to depend upon a novel molecule called Vanin-1 expressed by perivascular thymic stromal cells [2].

Associations of Vnn1 with chemical compounds

• We previously showed, using differential expression screening and in situ hybridization that Vanin-1, which encodes a glycosylphosphatidylinositol-linked membrane-associated pantetheinase, is expressed in a sex-specific manner during fetal gonad development in mice (Bowles, J., Bullejos, M., and Koopman, P. (2000) Genesis 27, 124-135) [7].
• Vanin-1(-/-) mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores [8].
• Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)) [6].
• Pantetheinase is an amidohydrolase involved in the dissimilative pathway of CoA, allowing the turnover of the pantothenate moiety [9].
• These mice lack the predominant epithelial pantetheinase isoform and have sharply reduced levels of cystamine/cysteamine in epithelial tissues [10].
• This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis [11].

Physical interactions of Vnn1

• We found that SF-1 is able to bind to two sites in the Vanin-1 promoter, whereas SOX9 can bind to a single interposed site defined by DNA footprinting [7].

Regulatory relationships of Vnn1

• The transcription factors steroidogenic factor-1 and SOX9 regulate expression of Vanin-1 during mouse testis development [7].
• In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region [6].

Other interactions of Vnn1

• The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant [6].
• The human gamma-globin gene promoter contains a stage selector element (SSE) responsible for preferential interaction of the promoter with a powerful erythroid-specific enhancer in the fetal developmental stage (S.M. Jane, P.A. Ney, E.F. Vanin, D.L. Gumucio, and A.W. Nienhuis. EMBO J. 11:2691-2699, 1992) [12].

References