Mad Tina
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB12536 | ENA |
REPOSITORIES: ENA
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Project description:Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments. Experiment Overall Design: Lung tumor tissue from TI-K (CCSP-rtTA;TRE-KrasV12), TI-KM (CCSP-rtTA; TRE-KrasV12; TRE-Mad2), recurrence (TI-KM) or normal lung tissue (CCSP-rtTA) was subjected to RNA extraction and individual samples hybridized to array platform MOE430A 2.0 Affymetrix.
2010-01-22 | E-GEOD-19753 | biostudies-arrayexpress
Project description:Inhibition of an initiating oncogene often leads to extensive tumor cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anti-cancer agents. Whether chromosomal instability (CIN) generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumors, has any effect on oncogene addiction, however, has not been explored systematically. We show here that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 does not affect the regression of Kras driven lung tumors upon Kras inhibition. However, tumors that experience transient Mad2 overexpression and consequent chromosome instability recur at dramatically elevated rates. The recurrent tumors are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early CIN may be responsible for tumor relapse after seemingly effective anti-cancer treatments.
2010-01-15 | GSE19753 | GEO
Project description:Mad2-induced chromosome instability leads to lung tumor relapse after oncogene withdrawal
| PRJNA122223 | ENA
Project description:rs10-04_mad - comparison of transcriptomes in mad mutants - What gene sets are differentially expressed in mad mutants? - Seeds of GFP171.1 (parental line), mad1, mad2, mad3, mad6 and dcl1-12 were sterilized and germinated on Murashige/Skoog medium with 0.9% agar. Plates were stratified at 4C in the dark for 4 days. The plates were then transferred to a growth cabinet at 21C under a 16h light/8h darkness light regime, and the seedlings were harvested 18 days after transfer to the growth cabinet.
2011-09-15 | GSE30477 | GEO
Project description:rs10-04_mad - comparison of transcriptomes in mad mutants - What gene sets are differentially expressed in mad mutants? - Seeds of GFP171.1 (parental line), mad1, mad2, mad3, mad6 and dcl1-12 were sterilized and germinated on Murashige/Skoog medium with 0.9% agar. Plates were stratified at 4C in the dark for 4 days. The plates were then transferred to a growth cabinet at 21C under a 16h light/8h darkness light regime, and the seedlings were harvested 18 days after transfer to the growth cabinet. 10 dye-swap - genotype comparaison
2011-09-14 | E-GEOD-30477 | biostudies-arrayexpress
Project description:RNF8 is downregulated in glioblastoma and low RNF8 expression correlates with poor patient prognosis. Overexpression (OE) of RNF8 in glioblastoma stem cell (GSC) impairs its proliferation and tumorigenicity, and the anti-cancer effects of RNF8 are dependent on both its FHA and RING domains. Paradoxically, transcriptomic analysis of RNF8 OE GSC reveals cell cycle as the top upregulated pathway. Mechanistically, RNF8 interacts with the mitotic checkpoint protein MAD2 in a RING domain-dependent manner to induce spindle assembly checkpoint (SAC) activation. RNF8 OE GSC displays increase level of aneuploidy and micronuclei formation, suggesting that RNF8 promotes chromosomal instability (CIN) in GSC through persistent SAC activation.
2022-12-10 | GSE190638 | GEO
Project description:<p>We employed next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his seven year course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ~1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation, PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression. ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies demonstrated increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy due to L869R mutation and increased migration due to ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a sub-clone metastasized early from the primary site and evolved independently in lymph nodes.</p>
| phs001159 | dbGaP
Project description:The centrosomal protein, CEP55 is a key regulator of cytokinesis and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/Cyclin B activation and CDK1-Caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis. Blocking MEK1/2-PLK1 signaling therefore reduced outgrowth of basal-like syngeneic and human breast tumors in in-vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2-PLK1 represents a potential therapeutic strategy for MYC-CEP55-dependent basal-like, triple-negative breast cancers.
2018-07-14 | GSE117058 | GEO
Project description:Glioblastoma (GBM) is a lethal brain tumor with remarkable intra-tumoral heterogeneity and therapeutic resistance which is linked to glioma stem cell (GSC). GSC contains unstable genome and elevated genomic instability could impair GSC self-renewal and tumorigenicity. In addition, GSC displays great dependency on BubR1, which is a key regulator of spindle assembly checkpoint (SAC) for proper chromosomal segregation. SAC prevents precocious anaphase progression in the presence of unattached kinetochores to ensure genomic integrity. To date, the regulation of SAC in GBM is still poorly understood and whether SAC could be exploited as a therapeutic target for GBM remains unknown. In our study, we revealed a previously unrecognized role of RNF8 in promoting SAC activation in GBM. GBM preferentially downregulates RNF8 in part by promoter methylation and low RNF8 expression correlates with inferior patient prognosis. Overexpression (OE) of wild-type RNF8 but not FHA and RING mutants significantly reduces GSC self-renewal, proliferation and tumorigenicity, and increases genomic instability. Mechanistically, the RING domain associates with the closed conformer of Mad2 (c-Mad2) and c-Mad2 exists as a complex with p31comet. CAMK2D binds transiently to the FHA domain via threonine 287 and this leads to RNF8 phosphorylation at serine 157. Furthermore, CAMK2D functions to recruit RNF8 to RNA splicing proteins to promote SAC activation independently of its enzymatic activity. To indirectly target RNF8-associated SAC in GBM, we exploited Connectivity Map (CMAP) and found that PLK1 inhibitor (PLK1i) could mimic RNF8-OE gene signature. Combination of PLK1i and proteostatic stressor leads to synergistic killing in GSCs. Collectively, our study unveiled an unconventional role of RNF8 in SAC regulation, dissected its molecular mechanisms and highlights the biological complexity of E3 ubiqtuitin ligases.
2023-07-21 | PXD038123 | JPOST Repository
Project description:Transcriptome analysis to map transcriptomes of Mad2 p53null-driven aneuploid liver cancers and T-ALLs, to determine correlation between copy number changes and expression changes and to map the transcriptional response to CIN Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.
2017-03-20 | GSE63687 | GEO