Uncovering the Role of PIM2 in Modulating MCL1 Dependency and Activation of ISR-Mediated NOXA Expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1105907 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28830200_1.fastq.gz | Fastqsanger.gz | |||
| SRR28830200_2.fastq.gz | Fastqsanger.gz | |||
| SRR28830189_1.fastq.gz | Fastqsanger.gz | |||
| SRR28830189_2.fastq.gz | Fastqsanger.gz | |||
| SRR28830190_1.fastq.gz | Fastqsanger.gz |
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Project description:Our study delves into the intricate dynamics of the integrated stress response (ISR) axis, focusing on the pivotal role of PIM2 kinase and its interaction with the BCL2 family of proteins, revealing crucial mechanisms governing cell survival and tumor progression. Elevated PIM2 expression is a hallmark of various cancers, often correlating with disease aggressiveness. Using a model of normal and malignant plasma cells, we unveil that inhibiting PIM2 kinase triggers not only the production of phosphorylated BAD but also activates ISR-mediated NOXA expression. This shift towards heightened dependence on MCL1 underscores the synergy achieved through combined PIM/MCL1 inhibition, largely propelled by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth, a response reversed by ISR-specific inhibition, concomitant with the upregulation of genes associated with tumor cell dissemination. These findings illuminate the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, particularly in tumors marked by elevated PIM2 expression.
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Project description:The anti-apoptotic MCL1 protein is a member of the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 protein is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. We attempted to identify acetylation as another critical post-translational modification regulating MCL1 protein stability. To this end, 293T cells were transfected with HA-humanMCL1 and Myc-p300. The whole-cell lysates were immunoprecipitated with anti-HA agarose beads. The immunoprecipitated material was resolved by SDS-PAGE, and the MCL1 band was excised for tryptic digestion followed by the MS analysis.
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Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs. This GEO dataset is comprised of aCGH measurements for DLBCL cell lines, which are used in the above-mentioned paper. Cell lines were measured against the DNA of a healthy male donor who in turn was measured against a pool of healthy DNAs to correct for individual CNVs of the donor.
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Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.
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Project description:Studies of miRNA profiling in the plasma of patients between ISR and non-ISR Venous blood was collected in EDTA in the ward or the cardiac catheterization laboratory before the angiography procedure and heparin administration. Plasma was harvested by centrifugation and stored at -80°C until assayed. Identical volumes of plasma from the 6 patients with ISR and 4 patients with non-ISR were pooled to reach a final volume of 1500µL for each patient. Total RNA was extracted using miRVana isolation kit, dephosphorylated and labeled using miRNA Complete Labeling kit. Scanning was achieved with the illumina iScan System. The result were acquired with the Genome Studio (GenomeStudioV2009.1).
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Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.
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Project description:In response to different cellular stressors, the ISR kinases, PERK, PKR, HRI and GCN2, activate downstream transcriptional programs. While the core ISR transcription program is well characterized, markers that are specific to each individual ISR kinase activation pathway are not known. To identify markers that are induced by PERK or GCN2, but not the other ISR kinases, we subjected WT, GCN2-/-, and PERK-/- MEFs to amino acid starvation (RPMI 1640 SILAC -Lys -Arg) or Thapsigargin (200nM) treatment for 6 hours to activate the GCN2 and PERK pathways, respectively and performed RNA sequencing.
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