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Perinuclear assembly of vimentin intermediate filaments induces cancer cell nuclear dysmorphia

ABSTRACT: Nuclear dysmorphia, characterized by crumpled or lobulated polymorphic nuclear shapes, has been used as an index for the malignant grades of certain cancers. The expression of vimentin, a type III intermediate filament protein, is a hallmark of the epithelial-to-mesenchymal transition. However, it remains unclear whether vimentin is involved in cancer cell nuclear dysmorphia. In this study, we found that vimentin intermediate filaments (VIFs) frequently accumulated at the concave of dysmorphic nucleus in breast cancer MDA-MB-231 cells. Depletion of vimentin apparently restored the nuclear shape of the cells, which was devastated by re-expression of vimentin, but not its assembly-defective Y117D mutant. Depletion of plectin, a cytoskeletal linker, partially prevented the perinuclear accumulation of VIFs and concomitantly restored the nuclear shape of the cells. In addition, depletion of vimentin in lung cancer A549 cells largely prevented nuclear dysmorphia during the epithelial-to-mesenchymal transition induced by transforming growth factor-β. Moreover, we found that VIF-mediated nuclear dysmorphia led to defects in DNA repair. Together, our results unveil a novel role of VIFs in cancer cell nuclear dysmorphia, which is associated with genome instability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279178 | GEO | 2024/11/15

REPOSITORIES: GEO

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	GSE279178_Read_Summary_FPKM.txt.txt.gz	Txt
	GSE279178_Read_Summary_Original_read_count.txt.txt.gz	Txt

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Expression of vimentin alters cell mechanics, cell-cell adhesion, and gene expression profiles suggesting the induction of a hybrid EMT in human mammary epithelial cells

Project description:Vimentin is a Type III intermediate filament (VIF) cytoskeletal protein that regulates the mechanical and migratory behavior of cells. Its expression is considered to be a marker for the epithelial to mesenchymal transition (EMT) that takes place in tumor metastasis. However, the molecular mechanisms regulated by the expression of vimentin in the EMT remain largely unexplored. We created MCF7 epithelial cell lines expressing vimentin from a cumate-inducible promoter to address this question. When vimentin expression was induced in these cells, extensive cytoplasmic VIF networks were assembled accompanied by changes in the organization of the endogenous keratin intermediate filament (KIF) networks and disruption of desmosomes. Significant reductions in intercellular forces by the cells expressing VIFs were measured by quantitative monolayer traction force and stress microscopy. In contrast, laser trapping micro-rheology revealed that the cytoplasm of MCF7 cells expressing VIFs was stiffer than the uninduced cells. Vimentin expression activated transcription of genes involved in pathways responsible for cell migration and locomotion. Importantly, the EMT related transcription factor TWIST1 was upregulated only in WT vimentin expressing cells and not in cells expressing a mutant non-polymerized form of vimentin, which only formed unit length filaments (ULF). Taken together, our results suggest that vimentin expression induces a hybrid EMT correlated with the upregulation of genes involved in cell migration.

2022-09-30 | GSE206724 | GEO

Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy

Project description:Anti-angiogenic anticancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Targeting of extracellular vimentin presents a promising anti-angiogenic immunotherapy strategy against cancer. Here we describe profiling of the HUVEC (Human Umbilical Vein Endothelial Cell) proteome, with special emphasis on vimentin (variants) in the different fractions. We have evidence that vimentin is externalized and deposited in the matrix of cultured cells and is as such available for targeted antiangiogenic therapeutics. The aim of the experiment is to determine the protein variants of vimentin in the cell, the secretome, and in the matrix deposited by the cells.

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CBFb Stabilizes HIV Vif to Counteract APOBEC3 at the Expense of RUNX1 Target Gene Expression [gene expression]

Project description:The HIV-1 accessory protein Vif hijacks a cellular Cullin-RING ubiquitin ligase, CRL5, to promote degradation of the APOBEC3 (A3) family of restriction factors. Recently, the cellular transcription cofactor CBFb was shown to form a complex with CRL5-Vif and to be essential for A3 degradation and viral infectivity. We now demonstrate that CBFb is required for assembling a well-ordered CRL5-Vif complex by inhibiting Vif oligomerization and by activating CRL5-Vif via direct interaction. The CRL5-Vif-CBFb holoenzyme forms a welldeﬁned heterohexamer, indicating that Vif simultaneously hijacks CRL5 and CBFb. Heterodimers of CBFb and RUNX transcription factors contribute toward the regulation of genes, including those with immune system functions. We show that binding of Vif to CBFb is mutually exclusive with RUNX heterodimerization and impacts the expression of genes whose regulatory domains are associated with RUNX1. Our results provide a mechanism by which a pathogen with limited coding capacity uses one factor to hijack multiple host pathways.

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CBFb Stabilizes HIV Vif to Counteract APOBEC3 at the Expense of RUNX1 Target Gene Expression [ChIP-seq]

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Project description:The seminal description of cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. As well as APOBEC3G and its homologues, however, we have recently discovered that Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E) (Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.

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CBFb Stabilizes HIV Vif to Counteract APOBEC3 at the Expense of RUNX1 Target Gene Expression [gene expression]

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CBFb Stabilizes HIV Vif to Counteract APOBEC3 at the Expense of RUNX1 Target Gene Expression [ChIP-seq]

2013-01-17 | E-GEOD-42575 | biostudies-arrayexpress

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