Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Moss, Joel; Vaughan, Martha

doi:10.1002/9780470123072.ch6

Cited by 140 publications

(39 citation statements)

References 512 publications

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“…Increased survival during taxol treatment was observed also in cells exposed to pertussis toxin, which uncouples the heterotrimeric inhibitory G protein, Gi from CD47 (Brown and Frazier 2001), and interrupts CD47-mediated signaling (Fig. 7D, lower panel; Moss and Vaughan 1988). Consistent with these findings, reversal of taxol resistance in clone 18 cancer cells by the 4N1K peptide also depended on the function of CD47, as anti-CD47 antibody abrogated this effect (Fig.…”

Section: Sensitization To Taxanes By Tsp-1 Is Signaled Through the CDsupporting

confidence: 70%

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Lih¹,

Wei²,

Cohen³

2006

Genes Dev.

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Using transcripts initiated at a chromosomally integrated retrovirus-based promoter to perturb gene expression randomly in human prostate cancer cells, we isolated cell clones resistant to taxane lethality and discovered the role of a previously uncharacterized gene, txr1, in this phenotype. We show that txr1 impedes taxane-induced apoptosis in tumor cells by transcriptionally down-regulating the production of thrombospondin-1 (TSP-1)-known earlier for both its anti-angiogenic and proapoptotic actions. Decrease of Txr1 or treatment with TSP-1 or TSP-1 mimetic peptide sensitized cells to taxane cytotoxicity by activating signaling through the CD47 receptor (also known as the integrin-associated protein), whereas interference with CD47 function reduced taxane-induced cell death. Cellular abundance of Txr1 and TSP-1 varied inversely, and alteration of the level of both proteins correlated highly with taxol resistance in 13 of 19 NCI-60 cancer cell lines. Our results reveal a hitherto unsuspected mechanism of taxane resistance, elucidate the role of txr1 in this resistance, and identify txr1 as a regulator of TSP-1 production and an agent for its chemotherapeutic modulation.[Keywords: Thrombospondin-1; CD47; taxanes; microarray; angiogenesis; Txr1] Supplemental material is available at http://www.genesdev.org. Taxanes are a family of major chemotherapeutic agents that have anti-neoplastic effects against a wide spectrum of human cancers (Rowinsky 1997). The anti-proliferative actions of the two clinically employed taxanes, paclitaxel (taxol) and docetaxel, stem from their ability to interact with ␤-tubulin and promote tubulin polymerization and stability; this event blocks cell cycling at the G 2 -M transition and results in eventual cell death by apoptosis (Horwitz 1992). Despite a dramatic response of susceptible tumors to initial treatment with taxanes, the subsequent development of resistance has proved to be a major limitation to long-term use of these agents as anticancer drugs (Horwitz et al. 1993). A widely studied mechanism associated with such resistance is the exclusion of taxanes and other drugs from cells by up-regulation of ATP-dependent cell membrane P-glycoproteins (i.e., transporter-related multidrug resistance [MDR]) (Bradley and Ling 1994). Genetic mutations that interfere with the binding of taxanes to microtubules have also been extensively investigated as a cause of taxol resistance (Giannakakou et al. 1997;Kavallaris et al. 1997;Ranganathan et al. 1998;Monzo et al. 1999).In recent years, several approaches that use functionbased screens for the discovery of cellular genes whose inactivation or overexpression yields phenotypic properties of interest have been developed (Li and Cohen 1996;Kimchi 2003;Primiano et al. 2003;Berns et al. 2004;Lu et al. 2004). One of these (Li and Cohen 1996) uses an experimentally regulated chromosomally integrated virus-based promoter to modulate the expression of genes at the site of viral insertion. Using this approach, we identified a previously unknown gene, tx...

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Section: Sensitization To Taxanes By Tsp-1 Is Signaled Through the CDsupporting

confidence: 70%

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Lih¹,

Wei²,

Cohen³

2006

Genes Dev.

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“…Like most bacterial pathogens, N. meningitidis synthesizes a number of toxic products believed to target and kill their host cells. Among these toxins, proteins that exert ADP-ribosylation activity represent a large family of potentially toxic enzymes able to modify or disrupt essential functions of eukaryotic cells (2). ADP-ribosyltransferases (ADPRTs) 3 catalyze the transfer of a single ADP-ribosyl group from ␤-nicotinamide adenine dinucleotide (NADϩ) onto specific amino acid residues of host cell proteins with the simultaneous release of nicotinamide (3).…”

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confidence: 99%

Structural and Biochemical Characterization of NarE, an Iron-containing ADP-ribosyltransferase from Neisseria meningitidis

Koehler

Carlier

Veggi

et al. 2011

Journal of Biological Chemistry

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NarE is a 16 kDa protein identified from Neisseria meningitidis, one of the bacterial pathogens responsible for meningitis. NarE belongs to the family of ADP-ribosyltransferases (ADPRT) and catalyzes the transfer of ADP-ribose moieties to arginine residues in target protein acceptors. Many pathogenic bacteria utilize ADP-ribosylating toxins to modify and alter essential functions of eukaryotic cells. NarE is further the first ADPRT which could be shown to bind iron through a Fe-S center, which is crucial for the catalytic activity. Here we present the NMR solution structure of NarE, which shows structural homology to other ADPRTs. Using NMR titration experiments we could identify from Chemical Shift Perturbation data both the NAD binding site, which is in perfect agreement with a consensus sequence analysis between different ADPRTs, as well as the iron coordination site, which consists of 2 cysteines and 2 histidines. This atypical iron coordination is also capable to bind zinc. These results could be fortified by site-directed mutagenesis of the catalytic region, which identified two functionally crucial residues. We could further identify a main interaction region of NarE with antibodies using two complementary methods based on antibody immobilization, proteolytic digestion, and mass spectrometry. This study combines structural and functional features of NarE providing for the first time a characterization of an iron-dependent ADPRT.

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“…Pretreatment of pancreatic islet preparations with pertussis toxin (PTX) 1 alleviates the inhibitory effects of some of these hormones, leading to the original description of PTX as islet-activating protein (3). PTX catalyzes the ADP-ribosylation of a cysteine residue near the C terminus of nearly all G␣ subunits of the G␣ i subfamily (4), suggesting that the inhibition of glucose-stimulated insulin secretion (GSIS) is mediated by G␣ i proteins. However, several reports indicate a lack of effect, or only a partial effect, of PTX pretreatment on inhibition of insulin secretion in islets (5)(6)(7)(8).…”

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confidence: 99%

A Role for Gz in Pancreatic Islet β-Cell Biology

Kimple

Nixon

Kelly

et al. 2005

Journal of Biological Chemistry

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Glucose-stimulated insulin secretion and ␤-cell growth are important facets of pancreatic islet ␤-cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein G z and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic ␤-cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which G␣ z impacts are intact in ␤-cells, and G␣ z activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) ␤-cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E (PGE1) is pertussis-toxin insensitive, indicating that other G␣ i family members are not involved in this process in this ␤-cell line. Indeed, overexpression of a selective deactivator of G␣ z , the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucosestimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by small interfering RNA-mediated knockdown of G␣ z expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13) ␤-cell line couples to G z predominantly and perhaps even exclusively. These data provide the first evidence for G z signaling in pancreatic ␤-cells, and identify an endogenous receptormediated signaling process in ␤-cells that is dependent on G␣ z function.Pancreatic islet ␤-cells are the sole producers of insulin in the body and thus play an important homeostatic role in the secretion of insulin in response to glucose and other secretagogues. Normally, the release of insulin from ␤-cells induces the peripheral tissues to take up available glucose from the plasma. Disregulation of this process can lead to the development of Type 2 diabetes, wherein the ␤-cells are unable to compensate for peripheral tissue insulin resistance, either through inadequate ␤-cell function and/or a decrease in ␤-cell mass (1).Certain hormones such as norepinephrine, somatostatin, galanin, and E prostaglandins decrease the secretion of insulin from ␤-cells in response to glucose (2). Pretreatment of pancreatic islet preparations with pertussis toxin (PTX) 1 alleviates the inhibitory effects of some of these hormones, leading to the original description of PTX as islet-activating protein (3). PTX catalyzes the ADP-ribosylation of a cysteine residue near the C terminus of nearly all G␣ subunits of the G␣ i subfamily (4), suggesting that the inhibition of glucose-stimulated insulin secretion (GSIS) is mediated by G␣ i proteins. However, several reports indicate a lack of effect, or only a partial effect, of PTX pretreatment on inhibition of insulin secretion in islets (5-8). This phenomenon of PTX insensitivity has been suggested to be because of insufficient PTX or too short a period of exposure (2), although an alternativ...

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Adp‐Ribosylation of Guanyl Nucleotide‐Binding Regulatory Proteins by Bacterial Toxins

Cited by 140 publications

References 512 publications

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Structural and Biochemical Characterization of NarE, an Iron-containing ADP-ribosyltransferase from Neisseria meningitidis

A Role for Gz in Pancreatic Islet β-Cell Biology

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