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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

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.

2020-07-02 | PXD017499 | Pride

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

Project description:Hepatitis B virus (HBV) is an enveloped, coated, non-cytopathic and hepatotropic partially double-stranded DNA virus in the family Hepadnaviridae genus Orthohepadnavirus. Despite significant progress in the availability of safe vaccines and antiviral therapies against HBV, it still affects approximately 257 million people worldwide and is responsible for about 887,000 deaths per year around the world [4]. HBV infection, which are associated with acute and chronic liver failure responses to viruses attacked the liver, can result in inactive carrier state, chronic hepatitis, or fulminant hepatitis and put them at high risk to develop advanced liver fibrosis and cirrhosis, and even hepatocellular cancer. Many viral factors, which could affect the disparity of clinical outcomes or disease prognosis during chronic HBV infection, have been reported in previous studies; among them, the viral genotype, as well as HBV mutations ascribing the virus to a certain phenotype, was reported to be the most important factor influencing viral pathogenesis, including the change of host immune recognition, the enhanced virulence with increased HBV replication and the facilitation of cell attachment or penetration.

2022-02-17 | PXD025968 | Pride

Serum proteomic profiling in patients with advanced Schistosoma japonicum-induced hepatic fibrosis

Project description:Background: Schistosoma japonicum (S. japonicum) is a parasitic flatworm that is the aetiological agent of human schistosomiasis, an important cause of hepatic fibrosis. Schistosomiasis-induced hepatic fibrosis is a consequence of the highly fibrogenic nature of egg-induced granulomatuous lesions, the main pathogenic factor of schistosomiasis. Although global awareness of the association between schistosomiasis-indued hepatic fibrosis and s. japonicum infection is increasing, little is known about the molecular differences associated with rapid progression to schistosomiasis in cirrhotic patients. Methods: We systematically used data-independent acquisition (DIA)-based liquid chromatography-mass spectrometry to identify differentially expressed proteins in serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. Results: On the basis of our analysis, we identified 1,144 proteins, among which 66 were differentially expressed between the healthy control and SHF-F2 groups and 214 were differentially expressed between the SHF-F2 and SHF-F4 groups (up- or downregulation of at least 1.5-fold in serum samples). Furthermore, our results indicated that two selected proteins (C1QA and CFD) are potential biomarkers for distinguishing patients with SHF-F2 and SHF-F4 resulting from S. japonicum infection. Conclusions: This report is the first to provide a global proteomic profile of serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. C1QA and CFD are potentially diagnostic markers for patients with SHF-F2 and SHF-F4 resulting from S. japonicum infection, although further large-scale studies are needed. Our DIA-based quantitative proteomic analysis revealed molecular differences among individuals with different stages of advanced S. japonicum-induced hepatic fibrosis and might provide fundamental information for further detailed investigations.

2022-09-06 | PXD025224 | Pride

Identification of dASF/SF2 potential mRNA targets

Project description:Deciphering the role of alternative splicing in developmental processes relies on the identification of key genes whose expression is controlled by splicing regulators throughout growth of a whole organism. Targeting expression of five SR proteins in the developing eye of Drosophila allowed us to show that these splicing factors induce various phenotypic alterations concerning eye organogenesis and viability. Although both dASF/SF2 and B52 caused defects in ommatidia structure, only B52 impairs normal photoreceptor axons projection and neurogenesis in visual ganglia. Consistently, microarray analyses revealed that many of the B52 targets are involved in brain organogenesis and we show that their splicing profile is altered both in B52 loss and gain of function. Conversely, a large proportion of dASF/SF2 targets are involved in eye development. This differential effect argues that SR proteins confer accuracy to developmental gene-expression programs, thus ensuring tissue identity and supporting cell-lineage decisions. Keywords: genetic modification Experiment aimed at identifying dASF/SF2 potential mRNA targets in the Drosophila developing eye Control: GMR X GFP-NLS trangenic larvae The 2 IP- GFP cy3 vs ASF cy5 rep.1 and IP- GFP cy5 vs ASF cy3 rep.1 samples correspond to dye-swap experiments. Two replicates (rep1 and rep2) are included.

2007-09-17 | E-GEOD-5857 | biostudies-arrayexpress

Identification of B52 potential mRNA targets

Project description:Deciphering the role of alternative splicing in developmental processes relies on the identification of key genes whose expression is controlled by splicing regulators throughout growth of a whole organism. Targeting expression of five SR proteins in the developing eye of Drosophila allowed us to show that these splicing factors induce various phenotypic alterations concerning eye organogenesis and viability. Although both dASF/SF2 and B52 caused defects in ommatidia structure, only B52 impairs normal photoreceptor axons projection and neurogenesis in visual ganglia. Consistently, microarray analyses revealed that many of the B52 targets are involved in brain organogenesis and we show that their splicing profile is altered both in B52 loss and gain of function. Conversely, a large proportion of dASF/SF2 targets are involved in eye development. This differential effect argues that SR proteins confer accuracy to developmental gene-expression programs, thus ensuring tissue identity and supporting cell-lineage decisions. Keywords: genetic modification Experiment aimed at identifying B52 potential mRNA targets in the Drosophila developing eye Control: GMR X GFP-NLS trangenic larvae The 2 IP- GFP cy3 vs B52 cy5 rep.1 and IP- GFP cy5 vs B52 cy3 rep.1 samples correspond to dye-swap experiments. Two replicates (rep1 and rep2) are included.

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Phosphoproteomics Data of pancreatic cancers cells treated with anlotinib

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Protein interactions with HA-tagged cytoplasmic dynein-2 DATASET2

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