Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity

ABSTRACT: Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable and justify the urgent need of new therapies. CDK5 functions a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin a5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130949 | GEO | 2019/08/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity

Project description:CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity

| PRJNA542104 | ENA

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.

Project description:Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bitransgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in b-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. The utility of this model is enhanced by ability to form tumor-derived allografts. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

2021-06-10 | GSE176448 | GEO

Cdk5 regulates activity-dependent gene expression and dendrite development [cultured cortical neurons]

Project description:To investigate the molecular mechanism underlying activity-dependent dendrite development regulated by Cdk5, an unbiased microarray analysis was performed to identify activity-dependent genes differentially regulated in cortical neurons from E18 Cdk5-knockout embryos.

2015-12-11 | GSE68320 | GEO

CDK5 inhibition abrogates TNBC stem-cell property and enhances anti-PD-1 therapy

Project description:Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that shows high infiltration of cancer stem cells (CSCs), which correlates with poor clinical outcome. Here, we have demonstrated that an aberrant activation of CDK5/pho-PPARg axis associated with TNBC progression closely. CDK5 blockade sufficiently abrogates stemness transformation of TNBC cells, resulting in a significant inhibition of tumor metastatic progression. Moreover, CDK5 inhibitor Rosc attenuates CD44v+ BCSCs, hereby reversing immunosuppressive microenvironment and enhancing anti-PD-1 effects on TNBC. Mechanistically, CDK5/pho-PPARgaxis modulates the ESRP1 degradation via E3 ligase-like activity, leading to CD44 variant (CD44v) expression. Our finding indicates that CDK5 blockade could be a potent strategy to target CSCs in TNBC, and to increase the response to PD-1 blockade in TNBC therapy.

2022-06-18 | GSE132902 | GEO

CDK5 activates Hippo signaling to confer resistance to radiotherapy via upregulating TAZ in lung cancer

Project description:Tumor resistance to radiotherapy is a therapeutic challenge in the treatment of patients with lung cancer. Cyclin-dependent kinase 5 (CDK5) has been proposed to participate in cell proliferation, migration and invasion; drug resistance; and immune evasion. However, the functions and regulatory mechanisms of CDK5 in lung cancer radioresistance have not been investigated.SiRNAs and ShRNAs were used to knock down CDK5 in A549 and H1299 cells. The effects of CDK5 depletion on the tumorigenic behaviors of non-small cell lung cancer (NSCLC) cells were evaluated in vitro and in vivo. Gene expression was examined by RNA-seq and quantitative real-time PCR.

2021-04-30 | GSE148532 | GEO

Different gene expression between CDK5 knocking down and control colorectal cancer cell line HCT116

Project description:We sought to find out the molecular mechanism of CDK5 displayed in colorectal cancer. Microarray experiments were carried out to identify different gene expression between CDK5-knockdown HCT116 cell lines and Scramble HCT116 cell lines.

2016-05-05 | GSE81085 | GEO

Adhesion GPCR, latrophilin-2, specifies cardiac lineage commitment through CDK5, Src, and P38MAPK

Project description:Identifying lineage-specific markers is pivotal for understanding developmental processes and developing cell therapies. Here, we report a new cardiomyogenic cell surface marker latrophilin-2 (Lphn2), an adhesion G protein-coupled receptor. When mouse and human pluripotent stem cells (PSCs) were stimulated with BMP4, Activin A, and bFGF, they differentiated into cardiac lineage cells. Lphn2 was selectively expressed on cardiac progenitor cells (CPCs) and cardiomyocytes (CMCs) during the differentiation of mouse PSCs, and cell sorting with an anti-Lphn2 antibody promoted the isolation of populations highly enriched in CPCs and CMCs. Lphn2 knock-down or knock-out PSCs did not express cardiac genes. To investigate the molecular mechanism underlying the induction of cardiac differentiation by Lphn2, we used the Phospho Explorer Antibody Array, which encompasses nearly all known signaling pathways. Lphn2-dependent phosphorylation was strongest for cyclin-dependent kinase 5 (CDK5) at Tyr15. We identified CDK5, Src, and P38MAPK as key downstream molecules of Lphn2. These findings provide a valuable tool for isolating cardiomyogenic progenitors and CMCs from PSCs and shed light on the still-unknown mechanisms of cardiac differentiation.

2017-01-06 | GSE92923 | GEO

Cyclin dependent kinase 5 (CDK5) regulates the circadian clock

Project description:We show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock via phosphorylation of PER2. CDK5 phosphorylated PER2 at serine residue 394 (S394) as shown by an in vitro kinase assay.

2019-12-04 | PXD012068 | Pride

PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway

Project description:Bladder cancer, one of the most diagnosed cancers worldwide, is associated with high morbidity, mortality, and a poor prognosis. The PIN1 phospho-dependent prolyl isomerase is frequently overexpressed in many human cancer types and affects tumor initiation and progression through disrupting the balance of oncoprotein and tumor suppressor protein signaling. However, the functional pSer/Thr.Pro protein substrates of PIN1 and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we discovered that ablation of Pin1 in human/mouse bladder cancer cells and organoids formed from mouse primary urothelial cells resulted in decreased cell proliferation, stemness maintenance, cell invasion, migration, urothelium clearance capacity, and reduced free/total cholesterol levels in vitro. Re-expressing Pin1 in Pin1 knockout cells reversed the defects caused by lack of Pin1. Moreover, in vivo subcutaneous xenograft and allograft transplantation mouse models combined with an orthotopic implantation model were utilized to confirm a positive role for Pin1 in controlling tumor growth and potential metastasis. Therapeutically, a combination of the sulfopin PIN1 inhibitor and the simvastatin HMGCR inhibitor was shown to suppress cell proliferation in vitro and tumor growth in vivo synergistically. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways in PIN1 knockout cells via RNA-sequencing and used a suite of diverse molecular and biochemical approaches to show that PIN1 interacts with JNK-dependent phosphorylated SREBP2 (Ser455) and vice versa. These results indicate that active cholesterol biosynthesis pathway in bladder cancer cells is regulated by PIN1-mediated isomerization and JNK-mediated phosphorylation of its key transcriptional factor SREBP2. These findings emphasize that PIN1 can act as a regulator and potential therapeutic target in bladder cancer.

2024-11-17 | GSE262761 | GEO

Elucidating molecular mechanisms underlying brain metastasis-promoting function of Cdk5

Project description:To elucidate molecular mechanisms underlying brain metastasis-promoting function of Cdk5, two analyses were performed. In the first analysis, we screened for Cdk5 substrates in brain-seeking breast cancer cell lines 4T1.Br3 and T11.Br1, transfected with shRNA targeting Cdk5 mRNA (100% knockdown) or control. T11.Br1 and 4T1.Br3 cells (shCDK5 or shCtl) were cultured for 6 days in the presence of labelled arginine and lysine from the SILAC Protein Quantitation Kit. For the second analysis, we performed a quantitative label-free mass-spectrometry analysis of astrocytes’ conditioned media pre-educated by 4T1.Br3 cell-derived CM for 72 h. For the second analysis, we performed a quantitative label-free mass-spectrometry analysis of astrocytes’ conditioned media pre-educated by 4T1.Br3 cell-derived CM for 72 h.

2024-06-28 | PXD053434 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data