Phospho-tyrosine signaling in mouse models of prostate cancer progression
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap, instrument model
ORGANISM(S): Mus Musculus (mouse)
DISEASE(S): Prostate Adenocarcinoma
SUBMITTER: 
Thomas Graeber
PROVIDER: PRD000615 | Pride | 2012-01-05
REPOSITORIES: Pride
Dataset's files
Items per page: 5 1 - 5 of 33 |
Publications
Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression.
Drake Justin M JM Graham Nicholas A NA Stoyanova Tanya T Sedghi Amir A Goldstein Andrew S AS Cai Houjian H Smith Daniel A DA Zhang Hong H Komisopoulou Evangelia E Huang Jiaoti J Graeber Thomas G TG Witte Owen N ON
Proceedings of the National Academy of Sciences of the United States of America 20120117 5
Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbe ...[more]
Similar Datasets
Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.
2023-10-11 | MTBLS8034 | MetaboLights
Project description:Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1 expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, organ morphogenesis appeared showed significant changes in AR-deficient Gli1-expressing cells. The transforming growth factor β (TGFβ) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGF- b signaling in AR deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.
2020-01-03 | GSE140823 | GEO
Project description:The ShcA adaptor possesses two phosphotyrosine binding motifs, which include an SH2 and a PTB domain. In the majority of cases, ShcA utilizes its PTB domain to engage activated receptor tyrosine kinases (RTKs). To establish the mportance of this domain during mammary tumorigenesis, we employed a ShcA mutant (R175Q) that no longer binds phospho-tyrosine residues via its PTB domain. We demonstrate that the ShcR175Q mutant delays mammary tumor onset n MMTV/MT transgenic animals. Paradoxically, we observe a robust increase in the growth and angiogenesis of emerging mammary tumors. ShcR175Q-expressing breast cancer cells increase fibronectin secretion and possess elevated levels f integrin α5/β1, the principle fibronectin receptor. Sustained integrin engagement activates Src, which in turn phosphorylates pro-angiogenic RTKs, including PDGFR, FGFR and Met, leading to increased VEGF secretion from ShcR175Q-xpressing breast cancer cells. Finally, we describe a ShcR175Q-dependent gene signature that stratifies breast cancer patients with a high microvessel density. This is the first study to demonstrate that intracellular signaling pathways ownstream of the ShcA PTB domain both positively and negatively regulate tumorigenesis during the various stages of breast cancer progression ShcA mutant (R175Q) vs NT/ShcA cells
2013-08-07 | E-GEOD-41718 | biostudies-arrayexpress
Project description:Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome. RNA-seq: HPr1-AR non-malignant, immortalized cell line +/- shRARG, +/- 10nM DHT for 0,24,96 hours
2018-07-20 | GSE117110 | GEO
Project description:Tau protein is a prominent component of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. While the abnormal phosphorylation of tau on serine and threonine has been well established in the disease process, its phosphorylation on tyrosine has only recently been described. We previously showed that the Src family non-receptor tyrosine kinases (SFKs) Fyn and Src phosphorylate tau on Tyr18 and that phospho-Tyr18-tau was present in AD brain. In this study, we have investigated the appearance of phospho-Tyr18-tau, activated SFK and proliferating cell nuclear antigen (PCNA) during disease progression in a mouse model of human tauopathy.We have used JNPL3, which expresses human tau with P301L mutation, and antibodies specific for phospho-Tyr18-tau (9G3), ser/thr phosphorylated tau (AT8), activated SFK and PCNA. Antibody staining was viewed by either epifluorescence or confocal microscopy.Phospho-Tyr18-tau appeared concurrently with AT8-reactive tau as early as 4 months in JNPL3. Some 9G3-positive cells also contained activated SFKs and PCNA. We also investigated the triple transgenic mouse model of AD and found that unlike the JNPL3 model, the appearance of 9G3 reactivity did not coincide with AT8 in the hippocampus, suggesting that the presence of APP/presenilin influences tau phosphorylation. Also, Thioflavin S-positive plaques were 9G3-negative, suggesting that phospho-Tyr18-tau is absent from the dystrophic neurites of the mouse triple transgenic brain.Our results provide evidence for the association of tyrosine-phosphorylated tau with mechanisms of neuropathogenesis and indicate that SFK activation and cell cycle activation are also involved in JNPL3.
| S-EPMC2939304 | biostudies-literature
Project description:Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome. RWPE1 non-malignant, immortalized cell line +/- shRARG, +/- 10nM CD437 for 24 hours
2018-07-20 | GSE117104 | GEO
Project description:Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome. RWPE-1 non-malignant prostate cell line +/- 30nM bi-NC or bi-96, Pulldown & Input (24 hr post-transfection)
2018-07-20 | GSE117103 | GEO
Project description:Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome. LNCaP malignant prostate cell line +/- shRARG, +/- 250nM CD437 for 24 hours
2018-07-20 | GSE117102 | GEO
Project description:Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome. ChIP-seq: RWPE-1-BAC-RARG-EGFP non-malignant, immortalized cell line infected with BAC-RARG-EGFP, +/- 10nM CD437 for 2 hours
2018-07-20 | GSE117179 | GEO
Project description:Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome. LNCaP malignant prostate cell line +/- 30nM bi-NC or bi-96, Pulldown & Input (24 hr post-transfection)
2018-07-20 | GSE117098 | GEO