A novel role of CDK2 inhibition in restraining microglial overactivation
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PROVIDER: PRJNA1029544 | ENA |
REPOSITORIES: ENA
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Project description:Neuroinflammation driven by microglial overactivation is a significant contributor across a diverse range of neurological disorders. While MEF2C mutations have been associated with a syndromic form of autism spectrum disorder (ASD) and various other neurological disorders in humans, the role of MEF2C as a key immune checkpoint to restrain microglial overactivation remains elusive. In this study, we established MEF2C-knockout (KO) induced microglia-like cells (iMGLs) via differentiation of corresponding human pluripotent stem cells, and subsequently treated with LPS, as a disease model of overactivated microglia. Through high-throughput screening, we identified BMS265246, a CDK2 inhibitor, which effectively normalized overactivated phenotypes in LPS-stimulated MEF2C-KO iMGLs, nearing levels seen in WT counterparts. Mechanistically, absence of MEF2C instigated a sequential cascade encompassing p21 downregulation, CDK2 activation, RB phosphorylation and degradation, and NF-κB p65 subunit nuclear translocation, thereby intensifying inflammatory responses. Remarkably, BMS265246 treatment significantly rectified microglial overactivation and ASD behavioral defects in both global and microglia-specific Mef2C heterozygous mice. Overall, our findings elucidate a novel protective mechanism governed by MEF2C, and unveil CDK2 as a promising therapeutic target for treating various diseases influenced by overactivated microglia with aberrant MEF2C expression and/or CDK2 activation.
2023-10-24 | GSE245677 | GEO
Project description:Background: Advanced gastrointestinal stromal tumor (GIST) is characterized by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximizing response to therapeutic CDK4/6 inhibition. Methods: Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4, and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterized in GIST cell lines after long-term exposure. Results: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK inhibitor resistance in GIST. Conclusions: These studies establish the biologic rationale for CDK2 and CDK4/6 co-inhibition as therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.
2022-11-01 | GSE206257 | GEO
Project description:MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggests that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
2018-06-06 | GSE107405 | GEO
Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.
2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress
Project description:Analysis of NB4 myeloid cells depleted for CDK2. Results provide insight into the role of CDK2 in myeloid cell differentiation. We used microarrays to detail the global programme of gene expression underlying CDK2-depletion induced differentiation and identified distinct classes of up-regulated genes during this process.
2018-12-31 | GSE64077 | GEO
Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics.
2014-05-19 | GSE16480 | GEO
Project description:Transcriptional profiling of isogenic human colorectal cancer cell line HCT-116, comparing parental cells, CDK2 knockout cells, cells treated with the CDK2-selective inhibitor NU6102 and cells resistant to 50µM NU6102. The aim was to compare effects of loss of CDK2 gene or kinase activity and determine potential mechanisms of inhibitor-resistance
2017-08-03 | GSE102165 | GEO
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Project description:The active form of the SREBP2 transcription factor was specifically overexpressed in the intesitne. This was achieved by generating transgenic mouse model (designated as ISR2) in which the transgene represents the N-terminal active SREBP2 transcription factor driven by the villin promoter. In this project, we investigated the effects of overactivation of SREBP2 on gene expression in mouse jejunum Gene expression profile in the jejunum of ISR2 was compared to gene expression profile in the jejunum of their wild type littermates.
2013-10-26 | E-GEOD-51736 | biostudies-arrayexpress
Project description:Halolamina pelagica strain:CDK2 Genome sequencing and assembly
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