Inhibitors and activators of ADP-ribosylation reactions

Banasik, Marek; Ueda, Kunihiro

doi:10.1007/978-1-4615-2614-8_25

Cited by 6 publications

(6 citation statements)

References 102 publications

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“…When transdifferentiation was allowed to occur and nicotinamide was added thereafter, 40±50 % of the cells which had switched from an acinar to a ductal phenotype were induced to regain acinar characteristics and lose ductal characteristics, which shows that the transdifferentiation is reversible. Nicotinamide, as well as 3-aminobenzamide and benzamide which we found to inhibit transdifferentiation, are potent inhibitors of ADP-ribosylation [38]. Involvement of ADP-ribosylation in differentiation processes has been described previously [39,40].…”

Section: Discussionsupporting

confidence: 61%

Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro

Rooman¹,

Heremans²,

Heimberg³

et al. 2000

Diabetologia

176

180

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Regeneration, or neogenesis, of beta cells in adult pancreas is an important research issue because it could find applications in the restoration of the normal beta-cell mass in diabetic patients. In vitro neogenesis might be a means of generating additional beta cells intended for transplantation, as the number of beta cells that can be isolated from organ donors is very limited. Neogenesis can be induced in vivo in several ways [1] but the identity of the beta-cell precursors is not clear. Several lines of evidence suggest that, in addition to duct cells, exocrine acinar cells could be able to transdifferentiate into beta cells [2]. In several experimental models and pathological conditions, islet neogenesis is accompanied by the transformation of the normal exocrine tissue into ductal complexes, a process called acinoductal metaplasia. This is seen in the model of pancreatic duct ligation [3], transforming growth factor-alpha transgenic mice [4,5] and interferon-gamma transgenic mice [6]. Islet neogenesis has also been observed in associ- Diabetologia (2000) Abstract Aims/hypothesis. In adult pancreatic regeneration models exocrine acini are found to transdifferentiate to duct-like complexes. This has also been associated with the formation of new endocrine islet cells. We aimed to establish an in vitro model in which this transdifferentiation process is characterised and can be modulated. Methods. Purified rat pancreatic acini were cultured in suspension. Differentiation was analysed by immunocytochemistry, electron microscopy, western blotting and RT-PCR.Results. During culture acinar cells directly transdifferentiated without dividing, the cells lost their acinar phenotype and started to express cytokeratins 20 and 7 and fetal liver kinase-1 (Flk-1) receptors for vascular endothelial growth factor. Expression of the acinar pancreatic exocrine transcription factor (PTF-1) remained and the pancreatic duodenal homeoboxcontaining transcription factor (PDX-1) was induced. When transdifferentiation was completed, the cells started to express protein gene product 9.5, a panneuroendocrine marker. By combining these features, the transdifferentiated cells show similar characteristics to precursor cells during active beta-cell neogenesis. We were able to modulate the differentiation state by addition of nicotinamide or sodium butyrate, agents which are known to stimulate endocrine differentiation in other models. Conclusion/interpretation. Here, we present an in vitro system in which the cellular differentiation of putative pancreatic endocrine precursor cells and their PDX-1 expression can be modulated, thereby providing a possible model for the study of beta-cell transdifferentiation. [Diabetologia (2000) Corresponding author: L. Bouwens, VUB-Department of Experimental Pathology, Laarbeeklaan 103, B-1090 Brussels, Belgium Abbreviations: BrdU, Bromodeoxyuridine; CK7, cytokeratin 7; CK20, cytokeratin 20; Flk-1, fetal liver kinase-1; PDX-1, pancreatic duodenal homeodomain containing transcription factor; PGP9.5, ...

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Section: Discussionsupporting

confidence: 61%

Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro

Rooman¹,

Heremans²,

Heimberg³

et al. 2000

Diabetologia

176

180

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“…Endogenous ADP ribosylation of G proteins leads to increased adenylyl cyclase activity (17, lS>, and ribosyltransferases have been proposed to function as endogenous regu .lators of G protei .nmediated functions. These enzymes are very sensitive to several inhibitors, including novobiocin, aminobenzimides, and the naphthoquinones (1). The 1,4-naphthoquinone used in the current study is loo-fold selective for the mono-ADP ribosyltransferases over poly-ADP ribosyltransferases (nuclear repair enzymes; 1).…”

Section: Discussionmentioning

confidence: 98%

Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide

Kanagy

Charpie

Dananberg

et al. 1996

American Journal of Physiology-Heart and Circulatory Physiology

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Nitric oxide (NO) has been postulated as a regulator of vascular reactivity, and the current study tested the hypothesis that NO-induced decreased sensitivity to vasoconstrictors persists following removal of NO. Endothelium-denuded segments of rat aorta were incubated 2-4 h at 37 degrees C with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). Incubation produced rightward shifts in concentration response curves for phenylephrine [i.e., half-maximum effective concentration (EC50; in microM): control = 0.016, NO = 0.14], aluminum fluoride (i.e., EC50 in mM: control = 1.66, NO = 2.29), and KCl (i.e., EC50 in mM: control = 5.9, NO = 23.9). Similar shifts were seen for two other NO donors. The SNAP-induced shift was not attenuated by a guanylyl cyclase inhibitor, LY-83583 (10 microM) and was not mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate (100 microM). It was attenuated by 1,4-naphthoquinone (50 microM), an inhibitor of endogenous mono-ADP ribosyltransferases. NO incubation increased cGMP content (4.6 +/- 0.8 vs. 1.5 +/- 0.15 pmol/mg protein), an increase unaffected by 1,4-naphthoquinone (3.3 +/- 1.0 pmol/mg protein) but prevented by LY-83583 (1.6 +/- 0.36 pmol/mg protein). ADP ribosylation of three proteins was observed in membranes from HEK 293 cells: 88,66, and 38 kDa. ADP ribosylation of the 38-kDa protein was stimulated in a concentration-dependent manner by NO but was not decreased by 1,4-naphthoquinone. In conclusion, NO produces a long-lasting inhibition of vascular contractility by both a cGMP-dependent and -independent mechanism. Based on the observations of 1,4-naphthoquinone, we conclude that the cGMP-independent mechanism is not stimulation of endogenous ADP ribosylation but some other covalent modification in the pathway that mediates contraction.

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“…We then tested a known inhibitor of mono-ADP ribosyltransferases, coumermycin A1 (ref. 18). Both the ADP ribosylation (Fig.…”

mentioning

confidence: 99%

Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Imai

Armstrong

Kaeberlein

et al. 2000

Nature

3,173

2,571

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Yeast Sir2 is a heterochromatin component that silences transcription at silent mating loci, telomeres and the ribosomal DNA, and that also suppresses recombination in the rDNA and extends replicative life span. Mutational studies indicate that lysine 16 in the amino-terminal tail of histone H4 and lysines 9, 14 and 18 in H3 are critically important in silencing, whereas lysines 5, 8 and 12 of H4 have more redundant functions. Lysines 9 and 14 of histone H3 and lysines 5, 8 and 16 of H4 are acetylated in active chromatin and hypoacetylated in silenced chromatin, and overexpression of Sir2 promotes global deacetylation of histones, indicating that Sir2 may be a histone deacetylase. Deacetylation of lysine 16 of H4 is necessary for binding the silencing protein, Sir3. Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, which deacetylate lysines 9 and 14 of H3 and specifically lysine 16 of H4. Our analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo. These findings provide a molecular framework of NAD-dependent histone deacetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.

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Inhibitors and activators of ADP-ribosylation reactions

Cited by 6 publications

References 102 publications

Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro

Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro

Decreased sensitivity to vasoconstrictors in aortic rings after acute exposure to nitric oxide

Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

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