Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA174342 | ENA |
REPOSITORIES: ENA
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Project description:The Pim (proviral integration site for Moloney murine leukemia virus) proteins form a serine threonine kinase family that regulates cell proliferation, migration and cell survival. Here we demonstrate for the first time that a Pim1 kinase plays an essential role in antiviral innate immune responses. Specifically, our in vivo, in vitro and RNA-sequencing analyses showed that Pim1 was quickly upregulated after Toll-like receptor (TLR) stimulation in a NF-kB-dependent manner and then promoted IFN-b production by forming a cell-surface complex composed of TRIF-signaling molecules and IRF3 that promoted IRF3 phosphorylation, nuclear translocation, and IFN-b production. As shown by Pim1 knockdown and knockout, Pim1 was essential for this role but its kinase activity was not involved. Pim1-deficiency increased the susceptibility of mice to poly I:C-induced sepsis. Our study uncovers a previously unrecognized role for Pim1 in antiviral innate immune responses, thus providing a new target for controlling viral infection.
2022-12-14 | GSE195582 | 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.
2023-12-04 | GSE237256 | GEO
Project description:Hepatoblastoma remains one of the most difficult childhood tumors to treat and is alarmingly understudied. Over half of patients initially present with locally advanced or metastatic disease and the prognosis for this cohort remains dismal. In addition, many of these children have disease that is resistant to standard therapies and will require novel and targeted therapies to effectively treat or manage their disease. We previously demonstrated that Proviral Insertion site in Maloney murine leukemia virus (PIM) kinases, specifically PIM3, are overexpressed in human hepatoblastoma cells and function to promote tumorigenesis. We aimed to use CRISPR/Cas9 gene editing technology with dual gRNAs to introduce large inactivating deletions in the PIM3 gene and achieve stable PIM3 knockout (KO) in the human hepatoblastoma cell line, HuH6. PIM3 KO of hepatoblastoma cells led to significantly decreased proliferation, viability, and motility, inhibited cell-cycle progression, decreased tumor growth in a xenograft murine model, and increased animal survival. Analysis of RNA sequencing data revealed that PIM3 KO downregulated expression of pro-migratory and pro-invasive genes and upregulated expression of genes involved in apoptosis and differentiation. Furthermore, PIM3 KO decreased hepatoblastoma cancer cell stemness as evidenced by decreased tumorsphere formation, decreased mRNA abundance of stemness markers, and decreased cell surface expression of CD133, a marker of hepatoblastoma stem cell-like cancer cells. Reintroduction of PIM3 into PIM3 KO cells rescued the malignant phenotype. These findings emphasize the role of PIM3 in promoting hepatoblastoma tumorigenesis and provide evidence that targeting PIM3 may offer a novel therapeutic approach for children with hepatoblastoma.
2021-10-27 | GSE164082 | GEO
Project description:Genome Instability Invites Murine Leukemia Virus Integration
| PRJNA280331 | ENA
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:PIM serine/threonine kinases are overexpressed, translocated or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types, and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBLC), follicular lymphoma (FL), marginal zone lymphoma-MALT type (MZL-MALT), chronic lymphocytic leukemia (CLL) and nodal marginal zone lymphoma (NMZL) cases. Increased PIM2 protein expression was associated with an aggressive clinical course in ABC-DLBCL patients. Pharmacological and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity, and indicated the involvement of PIM2 kinase in regulating mTORC1. The simultaneous genetic inhibition of all three PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. Gene-expression profiling was conducted in a series of 114 B-cell non-Hodgkin lymphoma patients (DLBCL, FL, MALT, MCL, CLL and NMZL). Seven freshly frozen lymph nodes and six freshly frozen reactive tonsils were used as controls.
2011-10-16 | E-GEOD-32018 | 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:Overexpression of Ecotropic Virus Integration site 1 protein homolog (EVI1) in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. We used an extracellular flux analyze to examine metabolic changes during leukemia development in a mouse model of MLL-r AML expressing high levels of Evi1 (Evi1+).
2018-08-04 | GSE118096 | GEO
Project description:The interactions between a retrovirus and host cell chromatin that underlie integration and provirus expression are poorly understood. The prototype foamy virus (PFV) structural protein GAG associates with chromosomes via a chromatin-binding sequence (CBS) located within its C-terminal region. Here, we show that the PFV CBS is essential and sufficient for a direct interaction with nucleosomes, and present a crystal structure of the CBS bound to a mono-nucleosome. The CBS interacts with the histone octamer, engaging the H2A-H2B acidic patch, in a manner similar to other acidic patch binding proteins such as herpesvirus latency-associated nuclear antigen (LANA). Substitutions of the invariant arginine anchor residue in GAG result in global re-distribution of PFV and macaque simian foamy virus (SFVmac) integration sites towards centromeres, dampening the resulting proviral expression without affecting the overall efficiency of integration. Our findings underscore the importance of retroviral structural proteins for integration site selection and the avoidance of genomic junkyards.
2017-05-10 | GSE97973 | GEO
Project description:PIM serine/threonine kinases are overexpressed, translocated or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types, and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBLC), follicular lymphoma (FL), marginal zone lymphoma-MALT type (MZL-MALT), chronic lymphocytic leukemia (CLL) and nodal marginal zone lymphoma (NMZL) cases. Increased PIM2 protein expression was associated with an aggressive clinical course in ABC-DLBCL patients. Pharmacological and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity, and indicated the involvement of PIM2 kinase in regulating mTORC1. The simultaneous genetic inhibition of all three PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.
2011-10-17 | GSE32018 | GEO