Safety profiling of genetically engineered Pim-1 kinase overexpression for oncogenicity risk in human c-kit+ cardiac interstitial cells
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PROVIDER: PRJNA512615 | ENA |
REPOSITORIES: ENA
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Project description:Bulk RNA-seq to profile of c-kit+ cardiac interstitial cells, comparing the transcriptomes of Pim-1 enhanced cardiac progenitor cells and transfection control
2019-01-04 | GSE124590 | GEO
Project description:PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity in inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.
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Project description:The aim of this study was to investigate the transciptional mechanisms regulated by three PIM kinases at singel cell level during early human Th17 cell differentiation. PIM kinases were transiently silenced using RNAi (KD) approach followed by single cell RNA-seq to determine the gene expression profile of PIM negative Th17 cells.
2023-11-23 | GSE231651 | GEO
Project description:The ERG gene belongs to the ETS family of transcription factors and has been found involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG,. We found that all the three ERG fusions significantly up-regulate PIM-1 expression in the NIH-3T3 cell line. PIM-1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM-1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM-1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM-1 induction. A significant association between ERG and PIM-1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM-1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM-1 expression. The up-regulation of PIM-1 induced by tERG over-expression significantly modified CyclinB1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after 24hrs of taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM-1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG together with the empty vector where profiled in triplicate. Quality control using NUSE and RLE plots identified one array as problematic (R540_TMP-ERG_P1) which was removed.
2011-11-30 | E-GEOD-32481 | biostudies-arrayexpress
Project description:The aim of this study was to investigate the transciptional mechanisms regulated by three PIM kinases during early human Th17 cell differentiation. PIM kinases were transiently silenced using RNAi (KD) approach followed by RNA-seq to determine their global transciptional targets.
2023-11-23 | GSE231650 | GEO
Project description:Phosphatidyl-inositol mannosides (PIM) are unique mycobacterial glycolipids. However, the PIM-induced immunostimulatory activities remain controversial. Here we report on gene expression analysis of monocyte-derived dendritic cells stimulated with tri-acylated PIM2 (AcPIM2) or tetra-acylated PIM2 (Ac2PIM2). Results provide evidence for the adjuvant activity of PIM.
2017-01-31 | GSE84740 | GEO
Project description:The ERG gene belongs to the ETS family of transcription factors and has been found involved in atypical chromosomal rearrangements in several cancers. To gain insight into the oncogenic activity of ERG, we compared the gene expression profile of NIH-3T3 cells stably expressing the coding regions of the three main ERG oncogenic fusions: TMPRSS2/ERG (tERG), EWS/ERG and FUS/ERG,. We found that all the three ERG fusions significantly up-regulate PIM-1 expression in the NIH-3T3 cell line. PIM-1 is a serine/threonine kinase frequently over-expressed in cancers of haematological and epithelial origin. We show here that tERG expression induces PIM-1 in the non-malignant prostate cell line RWPE-1, strengthening the relation between tERG and PIM-1 up-regulation in the initial stages of prostate carcinogenesis. Silencing of tERG reversed PIM-1 induction. A significant association between ERG and PIM-1 expression in clinical prostate carcinoma specimens was found, suggesting that such a mechanism may be relevant in vivo. Chromatin Immunoprecipitation experiments showed that tERG directly binds to PIM-1 promoter in the RWPE-1 prostate cell line, suggesting that tERG could be a direct regulator of PIM-1 expression. The up-regulation of PIM-1 induced by tERG over-expression significantly modified CyclinB1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after 24hrs of taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM-1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability.
2011-11-30 | GSE32481 | GEO
Project description:Gene expression profiling of diffuse large B-cell lymphoma (DLBCL)-derived cell lines exposed to the pan-PIM inhibitor MEN1703 was performed to investigate transcriptional consequences of PIM kinase inhibition in DLBCL and to identify treatment-related changes in the signalling pathways.
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Project description:PIM kinase inhibition in HCC xenograft
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Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using single shot DDA mass spectrometry we examine the impact of 24 hours treatment with two different pan-Pim kinase inhibitors PIM447 and AZD1208 on in vitro IL2 differentiated effector cytotoxic T lymphocytes. The Jak1/3 inhibitor tofacitinib was included as a control as this also blocks production of Pim kinases downstream of IL2. We find that treatment with pan-Pim kinase inhibitors has a similar phenotype to Pim1/Pim2 double deficiency, showing a reduction in proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecule Granzyme B and an increase in the translational repressor PDCD4.
2024-04-15 | PXD051214 | Pride