Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA122223 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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
Project description:Negative selection and chromosome instability induced by Mad2 overexpression delay breast cancer but facilitate oncogene independent outgrowth
| PRJEB12536 | ENA
Project description:Mad2 and p53 loss were combined in liver or T-cells specificely leading to early onset and highly aggressive aneuploid HCC and T-ALL. Tumours were characterized for (recurrrent) copy number changes with a focus on whole chromosome abnormalities. DNA content was compared to the DNA content of sex-matched uninfiltrated control liver samples from litter mates 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 | GSE63686 | GEO
Project description: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 | GSE63688 | GEO
Project description:MAP3K11 overexpression in tumors leads to weight loss in the host We assessed the ability of potential tumor maintenance genes to drive tumor growth in vivo using a directed complementation (DC) approach. This assay involves testing the ability of an introduced gene to maintain tumor growth when expression of an inducible driving oncogene is turned off. In this case, we tested the ability of MAP3K7/TAK1 or MAP3K11/MLK3 to form tumors in vivo in a genetically engineered model originally driven by a doxycycline-inducible HER2(V659E) oncogene. In this system, the expression and activity of HER2 was suppressed by doxycycline withdrawal and followed by the introduction of one of 13 genes (ErbB3, FAK1, FGFR2aIIIb, FGFR2aIIIc, FGFR3, HER2, MAP3K11, PIP5K1B, RONd160, RON+MSP, RSK2, MAP3K7, TNK2)
2015-04-23 | E-GEOD-68162 | biostudies-arrayexpress
Project description:Cryptococcus neoformans is an opportunistic, human fungal pathogen which undergoes fascinating switches in cell cycle control and ploidy when it encounters stressful environments such as the human lung. Here we carry out a mechanistic analysis of the spindle checkpoint which regulates the metaphase to anaphase transition, focusing on Mps1 kinase and the downstream checkpoint components Mad1 and Mad2. We demonstrate that Cryptococcus mad1D or mad2D strains are unable to respond to microtubule perturbations, continuing to re-bud and divide, and die as a consequence. Fluorescent tagging of Chromosome 3, using a lacO array and mNeonGreen-lacI fusion protein, demonstrates that mad mutants are unable to maintain sister-chromatid cohesion in the absence of microtubule polymers. Thus, the classic checkpoint functions of the SAC are conserved in Cryptococcus. In interphase, GFP-Mad1 is enriched at the nuclear periphery, and it is recruited to unattached kinetochores in mitosis. Purification of GFP-Mad1 followed by mass spectrometric analysis of associated proteins show that it forms a complex with Mad2 and that it interacts with other checkpoint signalling components (Bub1) and effectors (Cdc20 and APC/C sub-units) in mitosis. We also demonstrate that overexpression of Mps1 kinase is sufficient to arrest Cryptococcus cells in mitosis, and show that this arrest is dependent on both Mad1 and Mad2. We find that a C-terminal fragment of Mad1 is an effective in vitro substrate for Mps1 kinase and map several Mad1 phosphorylation sites. Some sites are highly conserved within the C-terminal Mad1 structure and we demonstrate that mutation of threonine 667 (T667A) leads to loss of checkpoint signalling and abrogation of the GAL-MPS1 arrest. Thus Mps1-dependent phosphorylation of C-terminal Mad1 residues is a critical step in Cryptococcus spindle checkpoint signalling. We conclude that CnMps1 protein kinase, Mad1 and Mad2 proteins have all conserved their important, spindle checkpoint signalling roles helping ensure high fidelity chromosome segregation.
2024-05-27 | PXD052327 | Pride
Project description:Neuroadaptations in the nucleus accumbens (NAc) underlie cue-induced cocaine craving that intensifies (“incubates”) during withdrawal and contributes to persistent relapse vulnerability. Long-lasting gene changes govern perpetual behavioral abnormalities but the role of epigenetic plasticity in cocaine craving during prolonged withdrawal is poorly understood. Here we show that chromatin remodeler INO80 in the NAc mediates cocaine-induced, withdrawal-dependent plasticity and incubated cocaine craving.
2019-10-29 | GSE119627 | GEO
Project description:Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
2020-03-30 | GSE130921 | GEO