Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA399641 | ENA |
REPOSITORIES: ENA
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Project description:Primary and secondary hypertension are major risk factors for cardiovascular disease. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we identify an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by dysregulated zonation of the glomerulosa, increased aldosterone levels and aldosterone target gene expression, and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a-/- mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of PIAS1, an E3 SUMO-protein ligase implicated in the suppression of LXR. Notably, SIAH1 sequence variants which impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression, were identified in patients with PA. The involvement of Siah1–PIAS1 in adrenal gland organization and function points to a possible new therapeutic target for hyperaldosteronism.
2018-05-01 | GSE102963 | GEO
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Project description:ARMC5 is a protein containing an armadillo domain (ARM) and a BTB domain. Its gene knockout caused many phenotypes, including dwarfism, compromise T-cell immunity, and adrenal gland hypertrophy. ARMC5 mutation in humans is associated with bilateral macronodular adrenal gland hypertrophy. We found that AMC5 KO mice suffered from an increased incidence of neural tube defects (NTDs). We revealed that ARMC5 complexed with CUL3 and POLR2A and was part of a novel POLR2A-specific ubiquitin ligase (E3). This E3 was the dominant DNA damage-independent POLR2A-specific E3 in developing neural tubes and neural precursor cells under a physiological condition. ARMC5 gene knockout (KO) caused diminished POLR2A ubiquitination and compromised POLR2A degradation via proteasomes. Surprisingly, the absence of this E3 did not lead to generalized Pol II stalling and the subsequent generalized decrease of mRNA transcription but caused an enlarged Pol II pool size, which dysregulated 108 genes in NPCs, including some known to neural development. ARMC5 KO in the intestine downregulated FOHL1 expression, which was essential in folate absorption. Whole-exome sequencing of 511 myelomeningocele (MM) patients revealed nine highly deleterious mutations in the ARMC5 coding sequence. A significant deleterious mutation Arg429Cys found in MM patients drastically weakened the interaction between ARMC5 and POLR2A, supporting our hypothesis that such mutations in ARMC5 increased the NTD risks by compromising the POLR2A-specific E3 activity. Our results indicated that this novel ARMC5-CUL3-RBX1 E3 played a critical role in Pol II pool homeostasis, and ARMC5 mutation was a modifier of NTD risks in mice and humans.
2023-12-01 | GSE169582 | GEO
Project description:ARMC5 is a protein containing an armadillo domain (ARM) and a BTB domain. Its gene knockout caused many phenotypes, including dwarfism, compromise T-cell immunity, and adrenal gland hypertrophy. ARMC5 mutation in humans is associated with bilateral macronodular adrenal gland hypertrophy. We found that AMC5 KO mice suffered from an increased incidence of neural tube defects (NTDs). We revealed that ARMC5 complexed with CUL3 and POLR2A and was part of a novel POLR2A-specific ubiquitin ligase (E3). This E3 was the dominant DNA damage-independent POLR2A-specific E3 in developing neural tubes and neural precursor cells under a physiological condition. ARMC5 gene knockout (KO) caused diminished POLR2A ubiquitination and compromised POLR2A degradation via proteasomes. Surprisingly, the absence of this E3 did not lead to generalized Pol II stalling and the subsequent generalized decrease of mRNA transcription but caused an enlarged Pol II pool size, which dysregulated 108 genes in NPCs, including some known to neural development. ARMC5 KO in the intestine downregulated FOHL1 expression, which was essential in folate absorption. Whole-exome sequencing of 511 myelomeningocele (MM) patients revealed nine highly deleterious mutations in the ARMC5 coding sequence. A significant deleterious mutation Arg429Cys found in MM patients drastically weakened the interaction between ARMC5 and POLR2A, supporting our hypothesis that such mutations in ARMC5 increased the NTD risks by compromising the POLR2A-specific E3 activity. Our results indicated that this novel ARMC5-CUL3-RBX1 E3 played a critical role in Pol II pool homeostasis, and ARMC5 mutation was a modifier of NTD risks in mice and humans.
2023-12-01 | GSE169350 | GEO
Project description:The ubiquitin ligase RNF5 regulates acute colitis through control of S100A8 stability
| PRJNA422424 | ENA
Project description:Loss of E3 ubiquitin protein ligase Cbl-b provides protection against UVB-induced cytotoxicity and inflammation.
| PRJNA314868 | ENA