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Phosphoproteomics Reveals the Wolframin-Calcium Axis as a Key Pathogenic Signaling Node in Primary Aldosteronism

ABSTRACT: Using 4D label-free quantitative proteomics technique, combined with bioinformatics, we generated in-depth proteome and phosphoproteome signaling network maps of aldosterone-producing adenoma and nonfunctioning adrenocortical tumor. We identified wolframin-calcium axis as a key regulatory node in aldosterone synthase activation and aldosterone hypersecretion.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Adrenal Adenoma Cell

SUBMITTER: 溢杨

LAB HEAD: Yang Yi

PROVIDER: PXD035691 | Pride | 2025-12-26

REPOSITORIES: Pride

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	S9450LPST_A10_Slot2-49_1_2236.d.zip	Other
	S9450LPST_A1_Slot2-40_1_2216.d.zip	Other
	S9450LPST_A2_Slot2-41_1_2220.d.zip	Other
	S9450LPST_A3_Slot2-42_1_2222.d.zip	Other
	S9450LPST_A4_Slot2-43_1_2224.d.zip	Other

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Publications

Phosphoproteomics Reveals the Wolframin-Calcium Axis as an Important Pathogenic Signaling Node in Primary Aldosteronism.

Ma Linqiang L Yang Shumin S Yang Yi Y Chen Xiangjun X Yang Jun J He Yifan Y Cheng Qingfeng Q Li Junlong J Kang Bing B Tang Siying S Zhang Aipin A Shu Xiaoyu X Li Xiaoyu X Shen Hang H Jing Ying Y Song Ying Y Li Qifu Q Hu Jinbo J

Hypertension (Dallas, Tex. : 1979) 20230224 5

<h4>Background</h4>Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown.<h4>Methods</h4>We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimen ...[more]

PMID: 36825503

Similar Datasets

proteomics Reveals the Wolframin-Calcium Axis as a Key Pathogenic Signaling Node in Primary Aldosteronism

Project description:Using 4D label-free quantitative proteomics technique, combined with bioinformatics, we generated in-depth proteome and phosphoproteome signaling network maps of aldosterone-producing adenoma and nonfunctioning adrenocortical tumor. We identified wolframin-calcium axis as a key regulatory node in aldosterone synthase activation and aldosterone hypersecretion.

2025-12-26 | PXD035656 | Pride

CGH analysis of adrenocortical tumors

2009-08-06 | GSE17396 | GEO

Constitutional variants and tumor-specific down-regulation of the calcium voltage-gated channel subunit CACNA1H in pheochromocytoma

Project description:Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here we re-analysed whole-exome sequencing data for PCC patients, and identified two patients with very rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in 7 PCC cases. Four of these were constitutional and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak staining or were negative. Furthermore, reduced CACNA1H gene expression was especially pronounced in PCC as compared to aPGL, in cases with normal norepinephrine levels and in PPGL with Cluster 2 kinase signalling phenotype. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles determined by mass spectrometry as well as a shift in the membrane potential where maximum calcium currents were observed as determined by electrophysiology. The findings add a possible novel genetic event to the growing palette of PPGL susceptibility genes and establish a potential link between the aetiology of adrenomedullary and adrenocortical tumor development.

2024-10-17 | PXD040446 | Pride

Primary Aldosteronism: Spatial Multiomics Mapping of Genotype-Dependent Heterogeneity and Tumor Expansion of Aldosterone-Producing Adenomas

Project description:Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). Here, we used spatial transcriptomics profiling of adrenal tissue cryosections to define the role of transcriptomic reprogramming in APA pathophysiology. Our findings advance the understanding of the transcriptional context of inter- and intra-tumoral APA heterogeneity and provide novel insight into the genotype-dependent tumor expansion capabilities of APAs.

2024-08-13 | GSE274314 | GEO

Modulation of calcium signalling on demand to decipher the molecular mechanisms of primary aldosteronism

Project description:Background. Primary aldosteronism is the most common form of secondary hypertension. The most frequent genetic cause of aldosterone producing adenoma (APA) are somatic mutations in the potassium channel KCNJ5. They affect the ion selectivity of the channel, with sodium influx leading to cell membrane depolarization and activation of calcium signalling, the major trigger for aldosterone biosynthesis. Methods. To investigate how KCNJ5 mutations lead to the development of APA, we established an adrenocortical cell model in which sodium entry into the cells can be modulated “on demand” using chemogenetic tools (H295R-S2 α7-5HT3 cells). We investigated their functional and molecular characteristics with regard to aldosterone biosynthesis and cell proliferation. Results. A clonal cell line with stable expression of the chimeric α7-5HT3 receptor in H295R-S2 cells was obtained. Increased sodium entry through the α7-5HT3 receptor upon stimulation with uPSEM-817 led to cell membrane depolarization, opening of voltage-gated Ca2+ channels and increased intracellular Ca2+ concentrations, resulting in the stimulation of CYP11B2 expression and increased aldosterone biosynthesis. Increased intracellular sodium influx did not increase proliferation, but rather induced apoptosis. RNA sequencing and steroidome analyses revealed unique profiles associated with Na+ entry, with only partial overlap with angiotensin II or potassium induced changes. Conclusion. H295R-S2 α7-5HT3 cells are a new model reproducing the major features of cells harbouring KCNJ5 mutations. Increased expression of CYP11B2 and stimulation of the mineralocorticoid biosynthesis pathway are associated with a decrease of cell proliferation and an increase of apoptosis, indicating that additional events may be required for the development of APA.

2025-01-19 | GSE282358 | GEO

Genomic alterations in primary hyperaldosteronism

Project description:Transcriptome comparison of an aldosterone producing adenoma transcriptome and its adjacent zona glomerulosa. Both tissues are from the same individual, are differentiated for aldosterone production, but the adjacent zona glomerulosa produces no aldosterone by negative feedback. Keywords = aldosterone producing adenoma transcriptome Keywords: parallel sample

2005-10-11 | GSE2017 | GEO

CGH analysis of adrenocortical tumors

Project description:Adrenocortical tumors are common; their prevalence may reach up to 5-7% in pathological series. Most of them are benign and hormonally inactive, however, rare hormone-secreting (aldosterone and cortisol) and malignant forms are associated with significant morbidity and mortality. The prognosis of adrenocortical cancer (ACC) is poor with an overall five-year survival below 30 %. In this study, CGH analysis was performed on 4 ACC (adrenocortical carcinoma), 4 IA (hormonally inactive adrenocortical adenoma) and 3 CPA (cortisol producing adrenocortical adenoma) samples. Tissue digestion, labeling, hybridization and data analysis of genomic DNA were performed according to the Agilent Technologies (Santa Clara, CA) protocol version 2.0 for 105 K arrays. As expected, many of the observed aberrations were generally consistent with those of other preciously published data and will provide the basis for determination how genomic diversity impacts biological function and human diseases, such as cancer. In this study, biopsies from adrenocortical tumors (4 ACC, 4 IA and 3 CPA samples) were analysed with CGH. Tissue digestion, labeling, hybridization, and data analysis of genomic DNA were performed according to the Agilent Technologies (Santa Clara, CA) protocol version 2.0 for 105 K arrays. Slides were scanned with Agilent Microarray scanner and data were extracted with Feature Extraction software version 9.5.1.1. DNA Analytics software was used (version 4.0.85, Agilent Technologies, Santa Clara, CA) for data analysis. The starting and ending points of the aberrations were confirmed by the ADM-2 algorithm with 6.0 threshold.

2010-05-15 | E-GEOD-17396 | biostudies-arrayexpress

Genomic alterations in primary hyperaldosteronism

2005-10-11 | E-GEOD-2017 | biostudies-arrayexpress

snRNAseq study of adrenal cortex adjacent to aldosterone-producing adenoma

Project description:To investigate the development of aldosterone-producing adenoma, we profiled cells of different areas of the adjacent adrenal cortex by snRNAseq to obtain possible trajectories towards adenoma formation.

2022-08-05 | GSE210381 | GEO

Human Adrenocortical Tumors: normal cortex vs inactive adenoma vs cortisol secreting adenoma vs adrenocortical cancer

Project description:Transcriptional profiling of human adrenocortical tumors. Gene expression profile of normal adrenal cortex, hormonally inactive adenoma, cortisol-secreting Cushing-adenoma and primary adrenocortical cancer tissues were compared. The goal of this study was to identify significant differences in the gene expression of these groups. Further aim was to reveal biologically relevant pathogenetic pathways altered at transcriptional and posttranscriptional level, as well.

2009-07-01 | GSE14922 | GEO