Nestin Promotes the Phosphorylation-dependent Disassembly of Vimentin Intermediate Filaments During Mitosis

Chou, Ying Hao; Khuon, Satya; Herrmann, Harald; Goldman, Robert D.

doi:10.1091/mbc.e02-08-0545

Cited by 175 publications

(164 citation statements)

References 51 publications

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“…Nestin contributes to the disassembly of vimentin during mitosis (54) inactivates the proapoptotic cyclin-dependent kinase 5 (55) and modulates mitosis-associated cytoplasmic reorganization during mitosis after becoming phosphorylated on Thr 316 by cdc2 kinase (56). Down-regulating nestin expression in neural progenitor cells inhibited cyclin D1/E expression (57).…”

Section: Discussionmentioning

confidence: 99%

Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis

Yamahatsu

Matsuda²,

Ishiwata

et al. 2012

Int J Oncol

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Abstract. The class VI intermediate filament protein, nestin is reported to be a progenitor cell marker in various tissues. In the present study, we analyzed the expression and roles of nestin in angiogenesis of pancreatic ductal adenocarcinomas, and determined whether nestin is a potential target for inhibiting tumor angiogenesis using a gene silencing strategy. Nestin expression was detected only in small vessels, whereas CD34, CD31 and factor VIII were also expressed in large-sized blood vessels in PDAC. The number of nestin-positive vessels was approximately 20% the number of CD34-positive vessels, and the average dimension of nestin-positive vessels was approximately 75% that of CD34-positive vessels. The PCNA labeling indices of nestin-positive vessels were higher than those of CD34-positive vessels and nestin-negative vessels. Reducing nestin expression by use of siRNA targeting nestin transcripts inhibited growth of the vascular endothelial cell lines, but there was no difference in cell motility. In xenograft models, administration of siRNA targeting mouse-nestin suppressed subcutaneous human pancreatic cancer cell growth in nude mice. In conclusion, nestin was expressed in small proliferating blood vessels in pancreatic cancer tissues and may be a useful marker of angiogenesis in pancreatic ductal adenocarcinoma tissues. Furthermore, nestin is a potential novel therapeutic target in pancreatic cancers to inhibit tumor angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis

Yamahatsu

Matsuda²,

Ishiwata

et al. 2012

Int J Oncol

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“…24 Nestin reportedly induces disassembly of vimentin to nonfilamentous aggregates or particles in mitotic Angiogenesis-specific nestin expression M Aihara et al cells for equal distribution of vimentin to daughter cells. 4 Thus, nestin expression appears to be proliferation-dependent in endothelium.…”

Section: Discussionmentioning

confidence: 99%

“…3 In copolymerized intermediate filaments, nestin induces disassembly of the vimentin filaments to nonfilamentous aggregates or particles in mitotic cells, suggesting that nestin plays a role in the distribution of vimentin filaments to daughter cells during progenitor cell division. 4 Nestin transgenepromoted b-galactosidase expression analysis in mice has revealed LacZ activity in neuroepithelium and somites shortly after neural tube closure (E9). 5 With this neural stem/progenitor cell-specific expression, nestin has been utilized to harvest neuronal progenitor cells from embryonal stem cells.…”

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confidence: 99%

Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene

Aihara

Sugawara

Torii

et al. 2004

Laboratory Investigation

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Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5 0 upstream promoter (5 0 UP) gave the highest activity, followed by 5 0 UP, and the second intron plus 5 0 UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.

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“…Following in vitro culture, nestin and vimentin are formed as a consequence of EMT-dedifferentiation into 'stem-like' mesenchymal cells (see [21]). This would imply that nestin cannot be regarded as a tissue-specific marker, but plays a general role in maintaining stem/progenitor cell properties by unequal partitioning of cytoplasmic components during cell division (see [38]). The finding that nestin-positive cells are generally formed in early differentiated ES cell derivatives in vitro [20], however, requires culture conditions that do not lead to the differentiation induction of neuronal cell types.…”

Section: Role Of Nestin In Epithelial-mesenchymal Transitions During mentioning

confidence: 99%

Generation of pancreatic insulin-producing cells from embryonic stem cells — ‘Proof of principle’, but questions still unanswered

2006

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Abbreviations E embryonal day EB embryoid body EMT epithelial-mesenchymal transition ES embryonic stemThe generation of insulin-producing cells from differentiating mouse embryonic stem (ES) cells was described some years ago [1], but subsequent studies could not replicate the results. Instead, using the same differentiation protocol, it was found that insulin immunoreactivity occurred as a consequence of insulin uptake from the medium [2], neuronal cells were formed [2-4], or insulin was released as an artefact from differentiated ES cells [2,3]. Functional pancreatic cells, however, were successfully generated using lineage selection strategies based on pancreas-specific promoters [5,6], by modified protocols in combination with transgene expression [7][8][9], or by addition of a phosphoinositol-3 kinase inhibitor [10]. The differentiated cells showed properties of (neonatal) beta cells, such as insulin transcripts and C-peptide/insulin co-expression, insulin-secretory granules, ion channel activity of embryonal beta cells, and normalisation of blood glucose level after transplantation into diabetic mice [5][6][7][8][9][10]. Most of the differentiation protocols required a long cultivation period, including 4-5 days of embryoid body (EB) formation, followed by 3-4 weeks of differentiation, and some protocols required genetic manipulation. Recently, a relatively short procedure of pancreatic differentiation by a three-step experimental approach was published [11]. The strategy is based on the combined treatment by activin A, all-trans-retinoic acid, and other factors such as basic fibroblast growth factor (bFGF), which induced murine ES cells to differentiate into insulin-producing cells within 2 weeks. The authors presented results on insulin transcripts, C-peptide/insulin co-expression, glucose-induced insulin release, and the normalisation of glycaemia following transplantation into diabetic mice. Neuronal vs pancreatic differentiation in vivo and of ES cells in vitroOn looking more closely at the C-peptide-positive cells differentiated according to the protocol of Shi et al. [11], it became obvious that both pancreatic and neuronal differentiation had been induced. In part, the clusters showed the typical morphology of grape-like structures, but also neuronal cell types (Fig. 1a). Immunohistochemical stainings revealed varying levels of co-expression of C-peptide, a byproduct of pro-insulin synthesis (used as a marker for insulin-producing cells), and the neuron-specific beta-III tubulin (Fig. 1b-g). Such ectoderm-derived insulin-producing (C-peptide-positive) cells have been generated from ES cells via EB formation, as well as from monolayer cultures

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Nestin Promotes the Phosphorylation-dependent Disassembly of Vimentin Intermediate Filaments During Mitosis

Cited by 175 publications

References 51 publications

Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis

Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis

Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene

Generation of pancreatic insulin-producing cells from embryonic stem cells — ‘Proof of principle’, but questions still unanswered

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