Functional and morphological changes induced by tunicamycin in dividing and confluent endothelial cells

Tiganis, Tony; Leaver, D. D.; Ham, K.; Friedhuber, Anna; Stewart, P. L.; Dziadek, Marie

doi:10.1016/0014-4827(92)90371-e

Cited by 15 publications

(12 citation statements)

References 45 publications

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“…Neo -vascularization is essential for normal growth and development, wound healing as well as for tumor growth and metastasis. N -glycans have been found to play an important role in capillary endothelial cell proliferation and tube formation [66,67,83-87], and N -glycosylation is highly sensitive to alterations in the ER luminal environment. Physiological states that increase the demand for protein folding, or stimuli that disrupt the reactions by which proteins fold, create an imbalance between the protein-folding load and the capacity of the ER, causing unfolded or misfolded proteins to accumulate in the ER lumen – a condition referred to as “ER stress”.…”

Section: Major Conclusionmentioning

confidence: 99%

N-glycans in cell survival and death: Cross-talk between glycosyltransferases

Banerjee

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

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Asparagine-linked (N-linked) protein glycosylation is one of the most important protein modifications. N-glycans with “high mannose”, “hybrid”, or “complex” type sugar chains participate in a multitude of cellular processes. These include cell–cell/cell–matrix/receptor–ligand interaction, cell signaling/growth and differentiation, to name a few. Many diseases such as disorders of blood clotting, congenital disorder of glycosylation, diseases of blood vessels, cancer, neo-vascularization, i.e., angiogenesis essential for breast and other solid tumor progression and metastasis are associated with N-glycan expression. Biosynthesis of N-glycans requires multiple steps and multiple cellular compartments. Following transcription and translation the proteins migrate to the endoplasmic reticulum (ER) lumen to acquire glycan chain(s) with a defined glycoform, i.e., a tetradecasaccharide. These are further modified, i.e., edited in ER lumen and in Golgi prior to moving to their respective destinations. The tetradecasaccharide is pre-assembled on a poly-isoprenoid lipid called dolichol, and becomes an essential component of the supply chain. Therefore, dolichol cycle synthesizing the lipid-linked oligosaccharide (LLO) is a hallmark for all N-linked glycoproteins. It is expected that there is a great deal of crosstalk between the participating glycosyltransferases and any missed step would express defective N-glycans that could have fatal consequences. The positive impact of the structurally altered N-glycans could lead to discovery of an N-glycan signature for a disease and/or help developing glycotherapeutic treating cancer or other human diseases. The purpose of this review is to identify the gaps of N-glycan biology and help developing appropriate technology for biomedical applications. This article is part of a Special Issue entitled Glycoproteomics.

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Section: Major Conclusionmentioning

confidence: 99%

N-glycans in cell survival and death: Cross-talk between glycosyltransferases

Banerjee

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…The TM-treated leukemic and endothelial cells showed similar changes in their rER; the accumulation of certain proteins was implicated in the rER [Morin et al, 1983;Tiganis et al, 1992]. Furthermore, disruption of rER and Golgi apparatus were seen in neurons of mouse cerebellar explants following 10 day incubation of TM [Carroll and Bird, 1991].…”

Section: N-glycosylation and Neuronal Ultrastructurementioning

confidence: 76%

Toxicity of tunicamycin to cultured brain neurons: Ultrastructure of the degenerating neurons

Lin

Wang

et al. 1999

J. Cell. Biochem.

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Our previous study has shown that tunicamycin irreversibly downregulates the expression of GABA A R and causes cell death in cultured brain neurons by biochemical and light microscopic methods. In this study, we examined mechanisms underlying the degeneration of the neurons mainly employing electron microscopic analysis. Cultured neurons derived from embryonic chicken brains were incubated with 5 µg/ml of tunicamycin (TM) for 24 h, followed by continual incubation or removal of TM for additional 3 h or 24 h. Neurons treated with TM for 24 h showed dilated rough endoplasmic reticulum (rER), nuclear envelope and components of Golgi apparatus, in addition to the degranulation of rER and disaggregation of ribosomal rosettes. In neurons subjected to the prolonged incubation, some ribosomes reattached to the membranes of rER; the polyribosomes reappeared, and the swelling of Golgi apparatus subsided. However, the distention of rER persisted, and an uncommon spindle-like structure appeared in the perikarya. This structure is implicated to involve the neuronal degeneration. Moreover, extracellular cell debris was increased with time of incubation. The ratio of the light neurons, defined as containing lower cytoplasmic matrix density than the untreated control, decreased from 28% at 3 h to 3% at 24 h after the removal of TM, and 45% at further 3 h to 6% at further 24 h incubation of TM, whereas dense neurons only appeared in the two 24 h groups, as 44% and 34%. The light neurons resemble necrotic cells, but the dense neurons exhibit distinct morphological features from necrosis and apoptosis. The gel electrophoresis assay revealed the absence of DNA fragmentation in all cultures. In addition, whole cell recordings exhibited a 40% decrease of the GABA-elicited current in the neurons exposed to TM for 24 h. The results indicate irreversible toxicity of chronic TM treatment to the neurons and suggest differential mechanisms for the neuronal death among various populations of cells. It is evident that the N-glycosylation plays a critical role for neuronal survival.

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“…N -linked glycoproteins have been found to play an important role in angiogenesis [23–27, 38, 39]. We have observed that proliferation of capillary endothelial cells as well as the capillary lumen formation is upregulated when the cells are treated with 8Br-cAMP [35, 30, 40].…”

Section: Discussionmentioning

confidence: 99%

“…Asparagine-linked glycoproteins have been found to play an important role in capillary endothelial cell proliferation and differentiation [23, 24). Furthermore, “hybrid” type but not “complex” type glycans are required for capillary tube formation [25–27].…”

Section: Introductionmentioning

confidence: 99%

Balancing life with glycoconjugates: Monitoring unfolded protein response-mediated anti-angiogenic action of tunicamycin by Raman spectroscopy

Longas

Kotapati

Prasad

et al. 2012

Pure and Applied Chemistry

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Asparagine-linked protein glycosylation is a hallmark for glycoprotein structure and function. Its impairment by tunicamycin [a competitive inhibitor of N-acetylglucosaminyl 1-phosphate transferase (GPT)] has been known to inhibit neo-vascularization (i.e., angiogenesis) in humanized breast tumor due to an induction of ER stress-mediated unfolded protein response (UPR). The studies presented here demonstrate that (i) tunicamycin (i) inhibits capillary endothelial cell proliferation in a dose dependent manner; (ii) treated cells are incapable of forming colonies upon its withdrawal; and (iii) tunicamycin treatment causes nuclear fragmentation. Tunicamycin-induced ER stress-mediated UPR event in these cells was studied with the aid of Raman spectroscopy, in particular, the interpretation of bands at 1672, 1684 and 1694 cm−1, which are characteristics of proteins and originate from C=O stretching vibrations of mono-substituted amides. In tunicamycin-treated cells these bands decreased in area as follows: at 1672 cm−1 by 41.85% at 3 h and 55.39% at 12 h; at 1684 cm−1 by 20.63% at 3 h and 40.08% at 12 h; and also at 1994 cm−1 by 33.33% at 3 h and 32.92% at 12 h, respectively. Thus, in the presence of tunicamycin, newly synthesized protein chains fail to arrange properly into their final secondary and/or tertiary structures, and the random coils they form had undergone further degradation.

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Functional and morphological changes induced by tunicamycin in dividing and confluent endothelial cells

Cited by 15 publications

References 45 publications

N-glycans in cell survival and death: Cross-talk between glycosyltransferases

N-glycans in cell survival and death: Cross-talk between glycosyltransferases

Toxicity of tunicamycin to cultured brain neurons: Ultrastructure of the degenerating neurons

Balancing life with glycoconjugates: Monitoring unfolded protein response-mediated anti-angiogenic action of tunicamycin by Raman spectroscopy

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