Mechanism of action of tunicamycin on the UDP-GlcNAc:dolichyl-phosphate GlcNAc-1-phosphate transferase

Heifetz, Aaron; Keenan, Roy W.; Elbein, Alan D.

doi:10.1021/bi00578a008

Cited by 400 publications

(245 citation statements)

References 27 publications

(31 reference statements)

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“…To test this hypothesis, we examined the effect of a set of small molecule inhibitors in HEK 293 and HL-1 cells expressing rat corin. As shown in Inhibition of Corin Activation in Tunicamycin-treated CellsTo assess the role of N-glycosylation in corin activation, stable HEK 293 cells expressing rat corin were cultured with or without tunicamycin, which blocks the protein N-glycosidic linkages by inhibiting the transfer of N-acetylglycosamine 1-phosphate to dolichol monophosphate (32). After a 16-h incubation at 37°C, the cells were lysed, and protein samples were analyzed by Western blotting under reducing and nonreducing conditions.…”

Section: Effects Of Small Molecule Inhibitors On Corin Activationmentioning

confidence: 99%

Role of Glycosylation in Corin Zymogen Activation

Liao

Wang

Chen

et al. 2007

Journal of Biological Chemistry

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The cardiac serine protease corin is the pro-atrial natriuretic peptide convertase. Corin is made as a zymogen, which is activated by proteolytic cleavage. Previous studies showed that recombinant human corin expressed in HEK 293 cells was biologically active, but activated corin fragments were not detectable, making it difficult to study corin activation. In this study, we showed that recombinant rat corin was activated in HEK 293 cells, murine HL-1 cardiomyocytes, and rat neonatal cardiomyocytes. In these cells, activated corin represented a small fraction of the total corin molecules. The activation of recombinant rat corin was inhibited by small molecule trypsin inhibitors but not inhibitors for matrix metalloproteinases or cysteine proteases, suggesting that a trypsin-like protease activated corin in these cells. Glycosidase digestion showed that rat and human corin proteins contained substantial N-glycans but little O-glycans. Treatment of HEK 293 cells expressing rat corin with tunicamycin prevented corin activation and inhibited its pro-atrial natriuretic peptide processing activity. Similar effects of tunicamycin on endogenous corin activity were found in HL-1 cells. Mutations altering the two N-glycosylation sites in the protease domain of rat corin prevented its activation in HEK 293 and HL-1 cells. Our results indicate that N-linked oligosaccharides play an important role in corin activation.

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Section: Effects Of Small Molecule Inhibitors On Corin Activationmentioning

confidence: 99%

Role of Glycosylation in Corin Zymogen Activation

Liao

Wang

Chen

et al. 2007

Journal of Biological Chemistry

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“…Furthermore, the former compounds were markedly more potent in terms of the inhibition of nucleolar RNA synthesis than were the latter anthracyclines. Thus, it is conceivable that the capacity to inhibit nucleolar RNA synthesis is related to the ability of marcellomycin and aclacinomycin to act as potent inducers of (Heifetz et al, 1979), led to the production of phenotypically mature cells. Retinoic acid, which also has the potential to interfere with the formation of lipid-linked oligosaccharide intermediates (Creek et al, 1983), is also a potent inducer of HL-60 leukaemia cell maturation (Collins et al, 1980).…”

Section: Squamous Cell Carcinoma As a Model Of Blocked Maturationmentioning

confidence: 99%

The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

Sartorelli¹

1985

Br J Cancer

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it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.

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“…Its mechanism of action is based on inhibition of N-acetyl glucosamine transfer from UDP-N-acetyl glucosamine to dolichol phosphate (Heifetz et al 1979) attached to the inner side of the endoplasmic reticulum Figure 1. Tunicamycin chemical structure and mechanism of its inhibitory action.…”

Section: Introductionmentioning

confidence: 99%

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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Abstract. In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/ VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides.

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Mechanism of action of tunicamycin on the UDP-GlcNAc:dolichyl-phosphate GlcNAc-1-phosphate transferase

Cited by 400 publications

References 27 publications

Role of Glycosylation in Corin Zymogen Activation

Role of Glycosylation in Corin Zymogen Activation

The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

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