Transcriptional response to aneuploidy in mouse epidermis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Floris Foijer
PROVIDER: E-GEOD-42698 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Analysis of the transcriptional response to aneuploidy in mouse epidermis. In this study we measured the transcriptional response to aneuploidy by aboragting the spindle checkpoint in mouse epidermis. We found that, whereas spindle checkpoint inactivation in the epidermis is tolerated, but results in metabolic deranged cells, SAC abrogation kills bulge stem cells
2013-01-22 | GSE42698 | GEO
Project description:Most human tumors have abnormal numbers of chromosomes, a condition known as aneuploidy. The mitotic checkpoint is an important mechanism that prevents aneuploidy through restraining the activity of the anaphase-promoting complex (APC). USP44 was identified as a key regulator of APC activation that maintains the association of MAD2 with the APC co-activator Cdc20. However, the physiological importance of USP44 and its impact on cancer biology are unknown. Here, we show that USP44 is required to prevent tumors in mice and is frequently down-regulated in human lung cancer. USP44 inhibits chromosome segregation errors independently of its role in the mitotic checkpoint by regulating proper centrosome separation, positioning, and mitotic spindle geometry, functions that require direct binding to the centriole protein, centrin. These data reveal a new role for the ubiquitin system in mitotic spindle regulation and underscore the importance of USP44 in the pathogenesis of human cancer. Study included 100 non-neoplastic (N) lung samples, and 69, 12, and 13 stage I, II, and II lung adenocarcinoma (AD) frozen tissues, respectively. Expression levels of Usp44 in different stages of AD was compared against N.
2013-09-01 | E-GEOD-40791 | biostudies-arrayexpress
Project description:Most human tumors have abnormal numbers of chromosomes, a condition known as aneuploidy. The mitotic checkpoint is an important mechanism that prevents aneuploidy through restraining the activity of the anaphase-promoting complex (APC). USP44 was identified as a key regulator of APC activation that maintains the association of MAD2 with the APC co-activator Cdc20. However, the physiological importance of USP44 and its impact on cancer biology are unknown. Here, we show that USP44 is required to prevent tumors in mice and is frequently down-regulated in human lung cancer. USP44 inhibits chromosome segregation errors independently of its role in the mitotic checkpoint by regulating proper centrosome separation, positioning, and mitotic spindle geometry, functions that require direct binding to the centriole protein, centrin. These data reveal a new role for the ubiquitin system in mitotic spindle regulation and underscore the importance of USP44 in the pathogenesis of human cancer.
2013-09-01 | GSE40791 | 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: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.
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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:Gametes are produced via meiosis, a specialized cell division associated with frequent errors which cause birth defects and infertility. Uniquely in meiosis I, homologous chromosomes segregate to opposite poles, usually requiring their linkage by chiasmata, the products of crossover recombination1. The spindle checkpoint delays cell cycle progression until all chromosomes are properly attached to microtubules2 but the steps leading to the capture and alignment of chromosomes on the meiosis I spindle remain poorly understood. In budding yeast meiosis I, Mad2 and Mad3BUBR1 are equally important for spindle checkpoint delay, but biorientation of homologs on the meiosis I spindle requires Mad2, but not Mad3BUBR1 3,4. Here we show that Mad3BUBR1 promotes accurate meiosis I homolog segregation outside its canonical checkpoint role, independently of Mad2. We find that Mad3BUBR1 associates with the TOGL1 domain of Stu1CLASP, a conserved plus-end microtubule protein which is important for chromosome capture onto the spindle. Homologous chromosome pairs that are proficient in crossover formation, but which fail to biorient, rely on Mad3BUBR1-Stu1CLASP to ensure their efficient attachment to microtubules and segregation during meiosis I. Furthermore, we show that Mad3BUBR1-Stu1CLASP are essential to rescue the segregation of mini-chromosomes lacking crossovers. Our findings define a new pathway ensuring microtubule-dependent chromosome capture and demonstrate that spindle checkpoint proteins safeguard the fidelity of chromosome segregation both by actively promoting chromosome alignment and delaying cell cycle progression until this has occurred.
2024-07-18 | PXD048251 | Pride
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: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.
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Project description:During metaphase, in response to improper kinetochore-microtubule attachments, the spindle assembly checkpoint (SAC) activates the mitotic checkpoint complex (MCC) to inhibit the anaphase-promoting complex/cyclosome (APC/C). The Mad1-Mad2 complex provides a catalytic platform for MCC assembly. Mad1-bound Mad2 recruits open-Mad2 through asymmetric dimerization and Mad1 phosphorylation by Mps1 promotes conversion of Mad2 from an open (O-Mad2) to closed (C-Mad2) state, which binds Cdc20 to form the MCC. How Mad1 phosphorylation catalytically activates MCC formation is poorly understood. This study characterises Mad1 phosphorylation by Mps1 and provides structural and biochemical insights into a phosphorylation-specific Mad1-Cdc20 interaction, which allows for a tripartite assembly of Bub1-Mad1-Cdc20 on the C-terminal domain of Mad1. We also identify a folded state of Mad1-Mad2 complex, suggesting a model by which the Cdc20-Mad1 interaction brings the Cdc20 MIM motif near Mad2. The Cdc20 MIM motif is then entrapped by the Mad2 safety belt to form a stable complex, allowing spontaneous MCC assembly.
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