Molecular Signature of Centrosome Abnormalities in Multiple Myeloma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Pavel Nemec
PROVIDER: E-MTAB-1038 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. genome-wide human SNP 6.0 arrays from Affymetrix was used to determine the copy number changes of MCF10A cells with extra centrosomes or depleted of MCAK after grown 4 days in 3-D cultures
2014-03-01 | E-GEOD-55042 | biostudies-arrayexpress
Project description:This experiment follows, extends and validates our previous findings published in Leukemia & Lymphoma as original article entitled \Molecular heterogeneity and centrosome-associated genes in multiple myeloma\. [Kryukov F, Nemec P, et al, Leuk Lymphoma. 2013 Sep;54(9):1982-8. Doi: 10.3109/10428194.2013.764416] (ArrayExpress Accession E-MTAB-1038). This experiment submission is enriched by supplemental R-script-based data file named \for_external_validation.RData\ which includes script for CAGP model application.
2016-05-01 | E-MTAB-4032 | biostudies-arrayexpress
Project description:Centrosome amplification induces proliferation arrest and cell invasion. The fate of centrosome amplification cells are studied here.
2021-10-07 | E-MTAB-11126 | biostudies-arrayexpress
Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
2014-03-01 | GSE55042 | GEO
Project description:The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.
2019-09-12 | PXD014829 | Pride
Project description:Centrosomal protein 120 (CEP120) is a 120kD centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome amplification, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.
2023-01-04 | GSE217567 | GEO
Project description:Despite the crucial importance of the centrosome in brain development and disease, its comprehensive proteome remains uncharacterized in neural cells. Here, we used spatial proteomics to elucidate protein interaction networks at the centrosome of iPSC-derived human neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell-type specific, with protein hubs involved in RNA-dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant splicing factor PRPF6 reproduced the periventricular misplacement in the developing mouse brain, highlighting mis-splicing of transcripts of the MAP-kinase SAD-A at centrosomal location as essential for the phenotype. Collectively, cell-type specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.
2022-06-15 | GSE201954 | GEO
Project description:Cyclin-dependent kinases (CDKs) complexed with cyclins drive progression through the eukaryotic cell cycle. From yeast to human cells, cyclin-CDK localises to the centrosome, but the importance of this localisation is unclear. The conserved ‘hydrophobic patch’ substrate docking site on human Cyclin B1 and on the equivalent fission yeast Cdc13 mediates their localisation to the centrosome and the spindle-pole body (SPB, yeast centrosome equivalent). A hydrophobic patch mutant (HPM) of Cdc13 cannot enter mitosis, but whether this mitotic defect is due to defective SPB localisation or defective cyclin-substrate docking is unknown. Here we show that artificially restoring Cdc13HPM SPB localisation in fission yeast partially rescues both mitosis and defective CDK substrate phosphorylation at both the SPB and within the cytoplasm. In addition, we found that an HPM of the S-phase cyclin Cig2 has defective SPB localisation but is still able to perform bulk DNA synthesis. Our results demonstrate that the hydrophobic patch mediates the SPB localisation of both S- and M-phase cyclins, and that Cdc13 SPB localisation is essential for mitotic entry and for full phosphorylation of CDK substrates, supporting the view that the centrosome plays a role as a signalling hub regulating CDK cell cycle control.
2024-04-04 | PXD044732 | Pride
Project description:Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of human cancer remains unclear. Here, we report the creation of a mouse model in which centrosome number can be persistently increased in the absence of additional genetic defects. We show that extra centrosomes increase tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive development of spontaneous tumors in multiple tissues. Tumors with centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship between centrosome amplification, genomic instability and tumor development. The sequences in this dataset result from random whole-genome DNA sequencing of spontaneous T- cell lymphomas, B-cell lymphomas, squamous cell carcinomas and one sarcoma from doxycycline-treated Plk4 mice.
2017-02-04 | E-MTAB-5043 | biostudies-arrayexpress
Project description:The presence of extra centrosomes is a feature of human tumours. However, it is unclear what are the changes elicited by the presence of these abnormalities. To determine the changes in gene expression induced by centrosome amplification, human mammary epithelial cells, MCF10A, expressing a doxycycline inducible PLK4 cDNA were used. Centrosome amplification was induced for 48 hrs upon the addition of doxycyclin to the culture medium. RNA was purified from MCF10A cells without extra centrosomes (no dox) and with extra centrosomes (dox) and processed for microarray analysis.
2018-02-10 | E-MTAB-6415 | biostudies-arrayexpress