Dual Blockade of the Lipid Kinase PIP4Ks and Mitotic Pathways Leads to Cancer-selective Lethality
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA412303 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We discover drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network Achieving robust cancer-specific lethality is the ultimate clinical goal. Here we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally up-regulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 up-regulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.
2018-02-23 | GSE104301 | GEO
Project description:Achieving robust cancer-specific lethality is the ultimate clinical goal. Here, we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally upregulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 upregulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131's ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.
| S-EPMC5736559 | biostudies-literature
Project description:A knockout-first model of H3f3a gene targeting leads to developmental lethality
| PRJNA891760 | ENA
Project description:Deficiency in Ybx1 Leads to Postnatal Lethality and IBD-like Disease in Zebrafish
| PRJNA554794 | ENA
Project description:BRD4 inhibition leads to MDSC apoptosis and enhances checkpoint blockade therapy.
| PRJNA1292467 | ENA
Project description:We compared the mRNAs expression profile of HeLa cells between two phases of the mitotic cell cycle: S and G2/M phases. Results provide insight into the regulation of transcript levels during mitotic cell cycle progression. HeLa cells were synchronized with double thymidine blockade (12 hours with 2 mM thymidine, 12 hours release, and 12 hours with 2 mM thymidine), and cells were taken after 2 hours release (S phase) and 8 hours release (G2/M phase). Keywords: time course Comparison of mRNAs measured at S phase (2 hours release after double thymidine blockade) and at G2/M phase (8 hours release after double thymidine blockade); 3 biological replicates at each of the two time points; two technical replicates with dye swapping per comparison; additional comparison between G2/M (8h) and S (2h).
2010-05-07 | E-GEOD-15547 | biostudies-arrayexpress
Project description:Selective compartmentalization in condensin-depleted mitotic chromosomes
| PRJNA949625 | ENA
Project description:Y box-binding protein 1 (Ybx1) is critical for embryogenesis and organogenesis. In zebrafish, we identify Ybx1 is predominantly expressed in the enterocytes of intestine in day5 larvae, whereas its immediately degradation driven by ubiquitination on day6. Here we show the maternal lethality with cardiac edema in ybx1-/- larvae, and postnatal larval lethality exhibited in ybx1-/- larvae within the death window from 10dpf to 20dpf. To study the underlying mechanisms for the ybx1-/- larvae partial lethality, we performed RNA-seq and experimental results showed the increased ROS might be the underlying cause for the postnatal lethality. By ascorbic acid treatment, we found ascorbic acid exposure prevented ybx1-/- larvae from postnatal lethality, while hydrogen peroxide aggravated ybx1-/- larvae postnatal lethality during the death window. By RNA-seq analysis, we also found significantly increased expressions of mmp9 and mmp13a in ybx1-/- larvae, and by inhibition of either MMP9 or MMP13a expression partially rescue the ybx1-/- postnatal lethality during the death window. Later, we further identify the intestinal impairs on 30 dpf and further deteriorated severe intestinal disorder in Ybx1 deficiency zebrafish. By exposure of ybx1-/- zebrafish for 14 days, we discover ascorbic acid partially mend the impaired intestine in ybx1-/-. In this study, we demonstrate that ybx1-/- larvae were ROS-susceptible, and the increased inflammation in ybx1-/- larvae intestine identified enables the ybx1-/- zebrafish as good model for studying of intestinal disease.
2020-12-15 | GSE134334 | GEO
Project description:Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in genomic stability can lead to tumor development and suggest that cell cycle regulators could be effective targets in anticancer therapy. However, many clinical trials ended in failure due to off-target effects of the inhibitors used. Here, we investigate in vivo the importance of WEE1- and MYT1-dependent inhibitory phosphorylation of mammalian CDK1. We generated Cdk1AF knockin mice, in which two inhibitory phosphorylation sites are replaced by the non-phosphorylatable amino acids T14A/Y15F. We uncovered that monoallelic expression of CDK1AF is early embryonic lethal in mice and induces S phase arrest accompanied by γH2AX and DNA damage checkpoint activation in mouse embryonic fibroblasts (MEFs). The chromosomal fragmentation in Cdk1AF MEFs does not rely on CDK2 and is partly caused by premature activation of MUS81-SLX4 structure-specific endonuclease complexes, as well as untimely onset of chromosome condensation followed by nuclear lamina disassembly. We provide evidence that tumor development in liver expressing CDK1AF is inhibited. Interestingly, the regulatory mechanisms that impede cell proliferation in CDK1AF expressing cells differ partially from the actions of the WEE1 inhibitor, MK-1775, with p53 expression determining the sensitivity of cells to the drug response. Thus, our work highlights the importance of improved therapeutic strategies for patients with various cancer types and may explain why some patients respond better to WEE1 inhibitors.
| S-EPMC6756125 | biostudies-literature
Project description:Replication stress, if not effectively and timely addressed, could result in DNA damage in mitosis. However, it remains unknown the relationship between mitotic DNA damage and other mitotic events such as nuclear envelope (NE) breakdown and reassembly. Here we report that replication stress could generate NE rupture. Rather than de novo formation, the rupture per se is a result of nuclear envelope reassembly defect (NERD) in mitosis. Repair of mitotic DNA damage by DNA polymerase theta (Polθ), a key microhomology-mediated end joining (MMEJ) factor, suppresses NERD. Furthermore, exacerbated NERD is observed in multiple conditions of synthetic lethality, suggesting NERD might be a general consequence of synthetic lethality. In addition, genomic mapping of LADs identifies a population of RESS-LADs (replication stress-sensitive LADs). Replication stress causes the loss of CFSs at RESS-LADs, likely due to the sustained phosphorylation of Lamin A/C at the NE rupture sites. Altogether, our findings establish a novel link between replication stress-induced genome instability and nuclear vulnerability.
2025-08-16 | GSE271990 | GEO