Showing papers by "Matthias Altmeyer published in 2010"
TL;DR: It is shown that in liver the activity of PARP-1, an NAD(+)-dependent ADP-ribosyltransferase, oscillates in a daily manner and is regulated by feeding and that Parp-1 knockout mice exhibit impaired food entrainment of peripheral circadian clocks.
316 citations
TL;DR: Computational and experimental results provide strong evidence that PARP1 modifies important regulatory lysines of the core histone tails of all core histones.
Abstract: The chromatin-associated enzyme PARP1 has previously been suggested to ADP-ribosylate histones, but the specific ADP-ribose acceptor sites have remained enigmatic. Here, we show that PARP1 covalently ADP-ribosylates the amino-terminal histone tails of all core histones. Using biochemical tools and novel electron transfer dissociation mass spectrometric protocols, we identify for the first time K13 of H2A, K30 of H2B, K27 and K37 of H3, as well as K16 of H4 as ADP-ribose acceptor sites. Multiple explicit water molecular dynamics simulations of the H4 tail peptide into the catalytic cleft of PARP1 indicate that two stable intermolecular salt bridges hold the peptide in an orientation that allows K16 ADP-ribosylation. Consistent with a functional cross-talk between ADP-ribosylation and other histone tail modifications, acetylation of H4K16 inhibits ADP-ribosylation by PARP1. Taken together, our computational and experimental results provide strong evidence that PARP1 modifies important regulatory lysines of the core histone tails.
247 citations
TL;DR: It is shown here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions.
Abstract: Gastric adenocarcinoma develops as a consequence of chronic inflammation of the stomach lining that is caused by persistent infection with the bacterium Helicobacter pylori. Gastric carcinogenesis progresses through a sequence of preneoplastic lesions that manifest histologically as atrophic gastritis, intestinal metaplasia, and dysplasia. We show here in several preclinical models of Helicobacter-induced atrophic gastritis, epithelial hyperplasia, and metaplasia that the inhibition of ADP ribosylation by the small-molecule inhibitor PJ34 not only prevents the formation of gastric cancer precursor lesions, but also efficiently reverses preexisting lesions. PJ34 exerts its chemopreventive and therapeutic effects by impairing Helicobacter-specific T-cell priming and T(H)1 polarization in the gut-draining mesenteric lymph nodes. The subsequent infiltration of pathogenic T cells into the gastric mucosa and the ensuing gastric T cell-driven immunopathology are prevented efficiently by PJ34. Our data indicate that PJ34 directly suppresses T-cell effector functions by blocking the IFN-gamma production of mesenteric lymph node T cells ex vivo. Upon exposure to PJ34, purified T cells failed to synthesize ADP-ribose polymers and to activate the transcription of genes encoding IFN-gamma, interleukin 2, and the interleukin 2 receptor alpha chain in response to stimuli such as CD3/CD28 cross-linking or phorbol 12-myristate 13-acetate/ionomycin. The immunosuppressive and chemoprotective effects of PJ34 therefore result from impaired T-cell activation and T(H)1 polarization, and lead to the protection from preneoplastic gastric immunopathology. In conclusion, ADP-ribosylating enzymes constitute novel targets for the treatment of Helicobacter-associated gastric lesions predisposing infected individuals to gastric cancer and may also hold promise for the treatment of other T cell-driven chronic inflammatory conditions and autoimmune pathologies.
35 citations
TL;DR: It is found in a mouse model of enterocolitis induced by S. Typhimurium that the absence of the nuclear protein poly(ADP-ribose) polymerase 1 (PARP1), a previously described cofactor for NF-κB-mediated proinflammatory gene expression, is associated with a delayed proinflammatory immune response after Salmonella infection.
Abstract: The immune system comprises an innate and an adaptive immune response to combat pathogenic agents. The human enteropathogen Salmonella enterica serovar Typhimurium invades the intestinal mucosa and triggers an early innate proinflammatory host gene response, which results in diarrheal disease. Several host factors, including transcription factors and transcription coregulators, are involved in the acute early response to Salmonella infection. We found in a mouse model of enterocolitis induced by S. Typhimurium that the absence of the nuclear protein poly(ADP-ribose) polymerase 1 (PARP1), a previously described cofactor for NF-κB-mediated proinflammatory gene expression, is associated with a delayed proinflammatory immune response after Salmonella infection. Our data reveal that PARP1 is expressed in the proliferative zone of cecum crypts, where it is required for the efficient expression of proinflammatory genes, many of which are related to interferon signaling. Consequently, animals lacking PARP1 show impaired infiltration of immune cells into the gut, with severely delayed inflammation.
31 citations
Patent•
11 Jan 2010
TL;DR: In this article, a blocker of Poly (ADPribose) Polymerase (PARP) was used to prevent and treat Helicobacter pylori induced gastric cancer.
Abstract: This invention relates to the prevention and treatment of Helicobacter pylori induced gastric cancer comprising administering a blocker of Poly (ADP-ribose) Polymerase (PARP), and the use of such blockers in said prevention and treatment and in the manufacture of medicaments for preventing and treating Helicobacter pylori induced gastric cancer.
Patent•
11 Jan 2010
TL;DR: La presente invention porte sur la prevention and le traitement d'un cancer gastrique induit par Helicobacter pylori, consistant a administrer un bloqueur de the poly(ADP-ribose)polymerase (PARP) and sur l'utilisation of tels bloqueurs pour ladite prevention et ledit traitement.
Abstract: La presente invention porte sur la prevention et le traitement d'un cancer gastrique induit par Helicobacter pylori, consistant a administrer un bloqueur de la poly(ADP-ribose)polymerase (PARP), et sur l'utilisation de tels bloqueurs pour ladite prevention et ledit traitement, ainsi que pour la fabrication de medicaments destines a prevenir et traiter un cancer gastrique induit par Helicobacter pylori.