Mice lacking vimentin develop and reproduce without an obvious phenotype

Colucci‐Guyon, Emma; Portier, Marie‐Madeleine; Dunia, I.; Paulin, Denise; Pournin, Sandrine; Babinet, Charles

doi:10.1016/0092-8674(94)90553-3

Cited by 568 publications

(411 citation statements)

References 43 publications

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“…Although non-cancerous mesenchymal cells also express vimentin, 50 vimentin appears to be dispensable for normal development and body function. 19,20 Therefore, we speculate that vimentin inhibition with WFA would have minimal toxic side effects in the clinic. Potentially, WFA can be combined with traditional chemotherapeutics and/or small molecular inhibitors to provide a multi-pronged approach that targets both tumor growth and metastasis.…”

Section: Cancer Therapymentioning

confidence: 95%

See 1 more Smart Citation

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

236

208

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Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 lM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.Metastatic disease is the major cause of death in almost all cancer types; however, most treatments are developed to target the primary tumor and not the metastases. This is due to metastatic cells being difficult to detect, highly aggressive, chemoresistant and experimentally challenging to model. 1 At present, there is no agent in clinical use that effectively prevents metastasis and most patients ultimately succumb to metastatic disease.The metastatic process can be broadly categorized into three stages-tumor cell invasion into surrounding tissue, intravasation into blood or lymphatic vessels and extravasation into a new host environment. These events are triggered by genetic and epigenetic alterations that transform stationary epithelial cells into migratory cells, a process termed epithelialmesenchymal transition (EMT). 2,3 Recent data suggests that cancer cells can re-trigger EMT to migrate into surrounding tissue. 3,4 A classical EMT protein is vimentin; numerous reports show that vimentin is overexpressed in invasive human tumors but is nearly undetectable in non-invasive, stationary tumors. 3,[5][6][7] Vimentin is a Type III intermediate filament 8 and its overexpression correlates with metastatic disease, EMT induction, poor prognosis and reduced patient survival. 7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer ce...

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Section: Cancer Therapymentioning

confidence: 95%

“…10,16,18 Furthermore, a vimentin knockout mouse has defective cell migration 19 without other obvious phenotypic consequences. 20 Overall, these attributes make vimentin a strong and novel candidate for pharmacological anti-invasion therapy.…”

mentioning

confidence: 99%

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

236

208

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“…These phosphorylation events are triggered by a wide range of protein kinases, such as PKA and PKC [15,19] [25] and involve a large number of serine residues (e.g. Ser 4,[6][7][8][9]25,33,38,41, 50, 55, 65, 71, 72, 82) with a complex pattern of overlapping specificities [15,26,27].Although vimentin appears involved in multiple cellular processes, mice lacking this protein are viable and do not show overt phenotypes [28]. Nonetheless, fibroblasts from vimentindeficient mice show mechanical instability and impaired ability to migrate and to contract a 3-D collagen network [29], thus providing a genetic evidence for the involvement of vimentin in cell plasticity and motility [30,31].…”

mentioning

confidence: 99%

“…Although vimentin appears involved in multiple cellular processes, mice lacking this protein are viable and do not show overt phenotypes [28]. Nonetheless, fibroblasts from vimentindeficient mice show mechanical instability and impaired ability to migrate and to contract a 3-D collagen network [29], thus providing a genetic evidence for the involvement of vimentin in cell plasticity and motility [30,31].…”

mentioning

confidence: 99%

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

et al. 2009

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Phosphoinositide 3-kinase c (PI3Kc) plays a fundamental role in mediating leukocyte migration to inflammation sites. However, the downstream cytoplasmic events triggered by its signaling activity are still largely obscure. To address this issue, tyrosine and serine/threonine phosphorylated proteins of chemokine-stimulated WT or PI3Kc-null macrophages were investigated. Among the proteins analyzed, the intermediate filament vimentin was found as a downstream effector of the PI3Kc signaling pathway. Specific analysis of the phosphorylation state of vimentin in macrophages showed that this protein becomes rapidly phosphorylated in both tyrosine and serine residues upon chemokine stimulation. In the absence of PI3Kc or the kinase activity of PI3Kc (PI3Kc KD/KD ), phosphorylation of vimentin was reduced. PI3Kc-null macrophages displayed impaired chemokine-driven vimentin fiber disassembly as well as reduced ability to transmigrate across endothelial cells. While WT macrophages infected with a vimentin mutant resistant to N-terminal serine phosphorylation showed a reduction in transendothelial migration, infection of PI3Kc-null macrophages with a vimentin mutant mimicking serine phosphorylation of N-terminal residues rescued the transendothelial migration defect. These results define vimentin N-terminal phosphorylation and fiber reorganization as a target of chemokine-dependent PI3Kc signaling in leukocytes.Key words: Cell migration . Intermediate filaments . Phosphoinositide 3-kinases .Signal transduction IntroductionPhosphoinositide 3-kinases (PI3K) are a family of ubiquitously expressed lipid and protein kinases. They are activated downstream transmembrane receptors [1] and are involved in several cellular responses such as metabolic regulation, survival, proliferation, cell migration and adhesion. PI3K convert PtdIns(4,5)P 2 into PtdIns(3,4,5)P 3 , a second lipid messenger product forming a docking site for various proteins harboring lipid binding modules such as the pleckstrin homology domain [2].Ã These authors contributed equally to this work. 1136Class I PI3K are heterodimeric proteins composed of a p110 catalytic subunit (a, b, g and d) and a regulatory adaptor subunit. According to their mechanism of activation, these enzymes can be further classified into two subclasses: while class IA PI3K (PI3Ka, b and d) include an adaptor protein of the p85 family and are activated by tyrosine kinase receptors, the sole known element of class IB, PI3Kg, is specifically activated by G protein-coupled receptors (GPCR) [3]. This effect is regulated by the interaction of PI3Kg with Gbg subunits of active G proteins through the involvement of either the p101 adaptor or its homologue p84/p87 [4]. Among mammalian tissues, the highest level of PI3Kg expression is found in leukocytes where this enzyme directs the chemotactic response to GPCR agonists [3]. Indeed, PI3Kg-null granulocytes show a significant reduction in chemotaxis toward chemokines and severely impaired bacteria-elicited peritoneal recruitment [5,6]. This migrati...

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“…21 Filensin is believed to be functionally important in the differentiation of LFCs and the maintenance of their conformation and transparency. 4,22,23 The intermediate filament vimentin does not appear to play a major role in lens function. Knockout of the lens' single vimentin gene in the mouse does not affect lens morphogenesis or the overall architecture of the LFCs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of gene expression in the ageing lens: a possible contributory factor in senile cataract

Segev

Mor²,

Segev

et al. 2004

Eye

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Purpose To study the molecular characteristics of lens epithelial cells from patients with senile cataract by cDNA microarray technique. Methods Lens epithelial cells adhering to anterior capsules taken during cataract surgery collected from 108 patients, aged 56À92 years (senile cataract group), were pooled. Pooled epithelial cells of normal, noncataractous lenses from one patient with ocular trauma, one patient with lens subluxation, and 25 cadaveric eyes, all under the age of 55 years, served as a control. Total RNA was extracted by conventional methods from the two groups of cells, and a fluorescent probe was prepared for each group. The probes were hybridized on 9700 known human cDNA clones. Hybridized clones were analysed using a scanning laser and the results were processed by GEMTools (Incyte Genomics) software. Results A total of 1827 clones hybridized with the two probes. Of these, 400 showed differences of more than two-fold in gene expression between the two probes. Relative to controls, gene expression in the senile cataract lenses was upregulated in 318 clones and downregulated in 82. Three genesfilensin, inwardly rectifying potassium channel (IRPC), and pigment epitheliumderived factor (PEDF) were strongly downregulated (by 41.3-, 6.8-, and 5.9-fold, respectively) in senile cataract. Conclusions Cataractogenesis is associated with numerous changes in the genetic profile of the lens epithelial cells. Since filensin, IRPC, and PEDF genes are known to have important roles in the physiology and morphology of the transparent lens, substantial downregulation of their expression might contribute to the formation of senile cataract.

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Mice lacking vimentin develop and reproduce without an obvious phenotype

Cited by 568 publications

References 43 publications

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Leukocyte transmigration is modulated by chemokine‐mediated PI3Kγ‐dependent phosphorylation of vimentin

Downregulation of gene expression in the ageing lens: a possible contributory factor in senile cataract

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