Amine Oxidase Copper-containing 1 (AOC1) Is a Downstream Target Gene of the Wilms Tumor Protein, WT1, during Kidney Development

Kirschner, Karin M.; Braun, Julian; Jacobi, C. A.; Rudigier, Lucas J.; Persson, Anja Bondke; Scholz, Holger

doi:10.1074/jbc.m114.564336

Cited by 21 publications

(19 citation statements)

References 67 publications

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“…Again, however, differences across studies complicate comparisons: the lack of reported associations with putrescine in previous population-based studies may be because it was not included on targeted assays or removed during quality control, because it was concentrated too lowly for quantification, because it was measured but not identified as putrescine, or because it showed no genetic associations and was therefore not reported. Although transcriptional activation of AOC1 has recently been linked to kidney morphogenesis in mice by affecting polyamine breakdown, 44 it cannot be inferred from our study whether elevated putrescine concentrations occur as a consequence of CKD or contribute causally to CKD etiology and/or progression.…”

Section: Discussionmentioning

confidence: 74%

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms

Sekula

Wuttke

et al. 2018

JASN

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The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions. We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD. After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines (, -min=2.4×10), a relatively high carrier frequency (2%) for rare deleterious missense variants in that are collectively associated with serum ratios of medium-chain acylcarnitines (-burden=6.6×10), and associations of a common variant in with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio (=2.2×10). The associations of this variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells. Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.

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Section: Discussionmentioning

confidence: 74%

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms

Sekula

Wuttke

et al. 2018

JASN

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“…Immunofluorescent stainings were performed on rat tissues as described in detail elsewhere (50,52,53). Briefly, rat embryos (15.5 dpc) and adult organs were flash-frozen in tissue-Tek O.C.T.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Wilms tumor protein–dependent transcription of VEGF receptor 2 and hypoxia regulate expression of the testis-promoting gene Sox9 in murine embryonic gonads

Kirschner¹,

Sciesielski

Krueger³

et al. 2017

Journal of Biological Chemistry

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Wilms tumor protein 1 (WT1) has been implicated in the control of several genes in sexual development, but its function in gonad formation is still unclear. Here, we report that WT1 stimulates expression of , the gene encoding VEGF receptor 2, in murine embryonic gonads. We found that WT1 and KDR are co-expressed in Sertoli cells of the testes and somatic cells of embryonic ovaries. Vivo-morpholino-mediated WT1 knockdown decreased transcripts in cultured embryonic gonads at multiple developmental stages. Furthermore, WT1 bound to the promoter in the chromatin of embryonic testes and ovaries. Forced expression of the WT1(-KTS) isoform, which functions as a transcription factor, increased mRNA levels, whereas the WT1(+KTS) isoform, which acts presumably on the post-transcriptional level, did not. ChIP indicated that WT1(-KTS), but not WT1(+KTS), binds to the promoter. Treatment with the KDR tyrosine kinase inhibitor SU1498 or the KDR ligand VEGFA revealed that KDR signaling represses the testis-promoting gene in embryonic XX gonads. WT1 knockdown abrogated the stimulatory effect of SU1498-mediated KDR inhibition on expression. Exposure to 1% O to mimic the low-oxygen conditions in the embryo increased expression but did not affect mRNA levels in gonadal explants. However, incubation in 1% O in the presence of SU1498 significantly reduced transcripts in cultured testes and increased levels in ovaries. These findings demonstrate that both the local oxygen environment and WT1, which enhances expression, contribute to sex-specific expression in developing murine gonads.

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“…11 AOC1 functions as a secreted diamine oxidase for the degradation of polyamines (such as putrescine and histamine), which are highly expressed in the kidneys, placenta, intestine, and lungs with lower levels in the brain. 12 Karin M. Kirschner et al report that AOC1 is involved in embryonic kidney morphogenesis and is transcriptionally regulated by the Wilms tumor transcription factor, WT1. 12 However, to the best of our knowledge, there has not been a study investigating the role of AOC1 in tumors.…”

Section: Introductionmentioning

confidence: 99%

“…12 Karin M. Kirschner et al report that AOC1 is involved in embryonic kidney morphogenesis and is transcriptionally regulated by the Wilms tumor transcription factor, WT1. 12 However, to the best of our knowledge, there has not been a study investigating the role of AOC1 in tumors. In this study, we first investigated the expression of AOC1 in human gastric cancer tissues by searching the Gene Expression Profiling Interactive Analysis (GEPIA) website.…”

Section: Introductionmentioning

confidence: 99%

<p>AOC1 Contributes to Tumor Progression by Promoting the AKT and EMT Pathways in Gastric Cancer</p>

Xu¹,

Xu²,

Xiong³

et al. 2020

CMAR

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Background: AOC1 is a copper-containing amine oxidase that is responsible for catalyzing the deamination of polyamines, which produces reactive oxygen species. Previous studies have demonstrated that polyamines are involved in the regulation of proliferation, migration, and apoptosis of cells. However, very little is known about the functions and regulatory mechanisms of AOC1 in tumors. Methods: Based on GEPIA data, we found that AOC1 was significantly upregulated in human gastric cancer tissues. We knocked down AOC1 in human AGS and MKN45 cells using siRNA transfection, then utilized qRT-PCR assay and Western blot to verify the effectiveness of AOC1 knockdown in gastric cancer cells. Results: Function analysis demonstrated that knockdown of AOC1 inhibited the proliferation, invasion, and migration of human gastric cancer cells. Flow cytometry detection suggested that AOC1 knockdown induced apoptosis in human gastric cancer cells. Mechanism investigation suggested that AOC1 knockdown increased the ratio of Bax/ Bcl2 and induced activation of the caspase cascade. Furthermore, the AKT signaling pathway was inactivated when AOC1 was silenced, including downregulated phosphorylation level of AKT and expression of downstream effectors, Cyclin D1, and p70S6K. Finally, we found that knockdown of AOC1 inhibited the epithelial-mesenchymal transition (EMT) in human gastric cancer by increasing the expression of epithelial markers E-cadherin, as well as decreasing mesenchymal marker N-cadherin, SNAIL and Slug. Conclusion: Our study suggests that AOC1 functions as an oncogene in human gastric cancer by activating the AKT signaling pathway and EMT process and maybe a target of 6-mercaptopurine, which provides new insight in the clinical use of AOC1 in gastric cancer therapy.

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Amine Oxidase Copper-containing 1 (AOC1) Is a Downstream Target Gene of the Wilms Tumor Protein, WT1, during Kidney Development

Cited by 21 publications

References 67 publications

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms

Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms

Wilms tumor protein–dependent transcription of VEGF receptor 2 and hypoxia regulate expression of the testis-promoting gene Sox9 in murine embryonic gonads

<p>AOC1 Contributes to Tumor Progression by Promoting the AKT and EMT Pathways in Gastric Cancer</p>

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