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Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

ABSTRACT: Activating mutations in NRAS account for 15-20% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Skin Melanoma

SUBMITTER: yalei wen

LAB HEAD: Yalei Wen

PROVIDER: PXD051431 | Pride | 2024-09-19

REPOSITORIES: Pride

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			Action	DRS
	U46-4.15-2.msf	Msf
	U46-4.15-2.raw	Raw
	U46-4.15-3.msf	Msf
	U46-4.15-3.raw	Raw
	WYL-CTRL-1.msf	Msf

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Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

Project description:Activating mutations in NRAS account for 20-30% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

2024-09-20 | PXD046277 | Pride

Comparative genomic hybridization of kidney samples from Wilms tumor patients to accurately map 1p13 breakpoints

Project description:Wilms tumour karyotypes frequently exhibit recurrent, large-scale chromosomal imbalances, among the most common of which are concurrent loss of 1p and gain of 1q. We have previously identified a novel breakpoint at 1p13 by 1Mb-spaced array CGH, and undertook a fine-tiling oligonucleotide array approach to accurately map the region in four tumours exhibiting rearrangements at this locus. The use of a 10 bpspaced platform revealed that all four tumours in fact harboured different breakpoints, which were mapped to target four distinct genes PHTF1, DCLRE1B, TRIM33 and NRAS. The precise breakpoint interval was confirmed for one case to lie within intron 3 of DCLRE1B by quantitative copy number PCR and RT-PCR. In addition, expression profiling revealed a pattern of down- and up-regulation of genes either side of the breakpoint in all cases. Although it appears that no single gene is the driver of this rearrangement, this study highlights the power of fine-tiling oligonucleotide arrays to delineate breakpoint regions identified by other genome-wide screens. Processed data is provided as one archive per processed data file obtained via clicking on the ftp link. Related experiment E-TABM-164.

2007-03-21 | E-TABM-155 | biostudies-arrayexpress

An integrated multi-omics analysis of identiﬁes distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa

Project description:Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and also cause chronic infections commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we profiled performed to assay for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To find the pivotal transcription factors that are likely involved in host immune defense, we integrally investigated systematic changes in chromatin accessibility and gene expression in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics studies. We discovered that Stat1 and Stat3 were altered in various omics and found similar results in mouse alveolar macrophages. Taken together, these findings indicate that these crucial transcription factors and their downstream signaling molecules play a critical role in the mobilization of host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, as well as provide clear insights and resources for using integrative histological analyses.

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Interacting proteins of SnRK2.4 by IP-MS

Project description:This project is designed to identify the interacting protein of SnRK2.4 through IP-MS.

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Comparative analysis of serum proteins between hepatitis B virus genotype B and C infection DIA-based quantitative proteomics

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2022-02-17 | PXD025968 | Pride

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Phosphoproteomics Data of pancreatic cancers cells treated with anlotinib

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Proteome and phosphoproteome of hippocampus after focal cerebral ischemia 2 h in mice

Project description:We obtained the profiles of neuronal phosphoproteome after cerebral ischemia onset by isolating mice hippocampus. Hippocampus combined from either ten sham or ten focal cerebral ischemia 2 h mice were lysed, digested, labeled with different TMT tags, then pooled and analyzed by LC/LC-MS/MS. Five percent of the pool was used for whole proteome analysis, and the remaining 95% was subjected to phosphoproteome profiling. In total, we quantified 5,174 proteins and 9,062 phosphopeptides. Interesting, 21 proteins were upregulated and 7 proteins were downregulated in hippocampus lysates of cerebral ischemia 2 h relative to sham base on fold change. S100a9, Alpha-2-HS-glycoprotein (Ahsg), Fibrinogen beta chain (Fga) and Complement Component C3(c3) are the top significantly changed, which were highly consistent with previous reports in cerebral ischemia injury. Using wolfpsort software to analysis the Subcellular Location, 57% of detected proteins were location to extracellular, 15% were cytoplasmic protein, another 11% were transport to nucleus, and the others were location to plasma membranes (10%), mitochondria (4%) and endoplasmic reticulum (3%). Moreover,184 phosphorylation sites of 135 proteins were upregulated and 689 phosphorylation sites of 420 proteins were downregulated in hippocampus during cerebral ischemia 2 h compare with sham operation. Employing wolfpsort software analysis the subcellular location, 50% of phosphorylated proteins were location to nucleus, 26% were cytoplasmic protein, another 16% were transport to plasma membranes, and the others were location to mitochondria (4%), extracellular (3%) and cytoskeleton (1%). Motif analysis showed that 85% were belongs to serine-type phosphorylation, about 14 were threonine-type phosphorylation and 1% were tyrosine-type phosphorylation.

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