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Poly-ADP-ribosylation in health and disease 总被引:6,自引:0,他引:6
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Poly(ADP-ribosyl)ation is required by multicellular eukaryotes to ensure genomic integrity under conditions of mild to moderate genotoxic stress. However, severe stress following acute neuronal injury causes overactivation of poly(ADP-ribose) polymerase-1, which results in unregulated poly(ADP-ribose) (PAR) synthesis and widespread neuronal cell death. Once thought to be a necrotic cell death resulting from energy failure, PARP-1 activation is now known to induce the nuclear translocation of apoptosis-inducing factor, which results in caspase-independent cell death. Conversely, poly(ADP-ribose) glycohydrolase, once thought to contribute to neuronal injury, now appears to have a protective role as demonstrated by recent studies utilizing gene disruption technology. Thus, the emerging mechanism dictating the fate of neurons appears to involve the regulation of PAR levels in neurons. Therefore, therapies targeting poly(ADP-ribosyl)ation in the treatment of neurodegenerative conditions such as stroke and Parkinson's disease are required to inhibit PAR synthesis and/or facilitate its degradation. 相似文献
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Aging appears to be an irreversible process. Here we report that nicotinamide (NAA) can induce rapid and reversible reversion
of aging phenotypes in human diploid fibroblasts in terms of cell morphology and senescence-associated β-galactosidase activity.
Although NAA seems to enhance the replicative potential of the cells, it has little effect on their growth rate and life span,
suggesting that NAA action is rather separated from the cellular replicative system. The effects are unique to NAA: none of
the NAA-related compounds examined (an NAD precursor/niacin, NAD analogs, and poly(ADP-ribose) polymerase inhibitors) exerted
similar effects. Thus, NAD-related metabolism and poly(ADP-ribosyl)ation are unlikely related to the NAA action. On the other
hand, histone acetyltransferase (HAT) activity was elevated in NAA-exposed cells, while in aged cells, HAT activity and histone
H4 acetylation were lowered. Taken together, the results suggest that NAA may cause rejuvenation by restoring, at least in
part, altered gene expression in aged cells through its activation of HAT.
Received 27 August 2001; received after revision 15 October 2001; accepted 15 October 2001 相似文献
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Blenn C Wyrsch P Bader J Bollhalder M Althaus FR 《Cellular and molecular life sciences : CMLS》2011,68(8):1455-1466
Oxidative DNA damage to cells activates poly(ADP-ribose)polymerase-1 (PARP-1) and the poly(ADP-ribose) formed is rapidly degraded
to ADP-ribose by poly(ADP-ribose)glycohydrolase (PARG). Here we show that PARP-1 and PARG control extracellular Ca2+ fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation
accounts for essentially the entire Ca2+ influx into the cytosol, activating caspases and causing the translocation of apoptosis inducing factor (AIF) from the inner
mitochondrial membrane to the nucleus followed by cell death. Abrogation of PARP-1 or PARG function disrupts these signals
and reduces cell death. ADP-ribose-loading of cells induces Ca2+ fluxes in the absence of oxidative damage, suggesting that ADP-ribose is the key metabolite of the PARP-1/PARG system regulating
TRPM2. We conclude that PARP-1/PARG control a cell death signal pathway that operates between five different cell compartments
and communicates via three types of chemical messengers: a nucleotide, a cation, and proteins. 相似文献
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Cohausz O Blenn C Malanga M Althaus FR 《Cellular and molecular life sciences : CMLS》2008,65(4):644-655
Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor
(AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR
molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we
determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG),
the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2
and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems
to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.
Received 7 November 2007; received after revision 19 December 2007; accepted 21 December 2007
O. Cohausz, C. Blenn: These two authors contributed equally to this work. 相似文献
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Poly-ADP-ribosylation in health and disease 总被引:4,自引:0,他引:4
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Rosy El Ramy Najat Magroun Nadia Messadecq Laurent R. Gauthier François D. Boussin Ullas Kolthur-Seetharam Valérie Schreiber Michael W. McBurney Paolo Sassone-Corsi Françoise Dantzer 《Cellular and molecular life sciences : CMLS》2009,66(19):3219-3234
Poly(ADP-ribose) polymerase-1 (Parp-1) and the protein deacetylase SirT1 are two of the most effective NAD+-consuming enzymes in the cell with key functions in genome integrity and chromatin-based pathways. Here, we examined the
in vivo crosstalk between both proteins. We observed that the double disruption of both genes in mice tends to increase late
post-natal lethality before weaning consistent with important roles of both proteins in genome integrity during mouse development.
We identified increased spontaneous telomeric abnormalities associated with decreased cell growth in the absence of either
SirT1 or SirT1 and Parp-1 in mouse cells. In contrast, the additional disruption of Parp-1 rescued the abnormal pericentric
heterochromatin, the nucleolar disorganization and the mitotic defects observed in SirT1-deficient cells. Together, these
findings are in favor of key functions of both proteins in cellular response to DNA damage and in the modulation of histone
modifications associated with constitutive heterochromatin integrity. 相似文献
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Berger W Steiner E Grusch M Elbling L Micksche M 《Cellular and molecular life sciences : CMLS》2009,66(1):43-61
The unique and evolutionary highly conserved major vault protein (MVP) is the main component of ubiquitous, large cellular
ribonucleoparticles termed vaults. The 100 kDa MVP represents more than 70% of the vault mass which contains two additional
proteins, the vault poly (ADP-ribose) polymerase (vPARP) and the telomerase-associated protein 1 (TEP1), as well as several
short untranslated RNAs (vRNA). Vaults are almost ubiquitously expressed and, besides chemotherapy resistance, have been implicated
in the regulation of several cellular processes including transport mechanisms, signal transmissions and immune responses.
Despite a growing amount of data from diverse species and systems, the definition of precise vault functions is still highly
complex and challenging. Here we review the current knowledge on MVP and vaults with focus on regulatory functions in intracellular
signal transduction and immune defence.
Received 27 June 2008; received after revision 25 July 2008; accepted 30 July 2008 相似文献
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R. T. Allen M. W. Cluck D. K. Agrawal 《Cellular and molecular life sciences : CMLS》1998,54(5):427-445
Apoptosis is an essential and highly conserved mode of cell death that is important for normal development, host defense
and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in degenerative conditions, vascular diseases,
AIDS and cancer. Among the numerous proteins and genes involved, members of the Bcl-2 family play a central role to inhibit
or promote apoptosis. In this article, we present up-to-date information and recent discoveries regarding biochemical functions
of Bcl-2 family proteins, positive and negative interactions between these proteins, and their modification and regulation
by either proteolytic cleavage or by cytosolic kinases, such as Raf-1 and stress-activated protein kinases. We have critically
reviewed the functional role of caspases and the consequences of cleaving key substrates, including lamins, poly(ADP ribose)
polymerase and the Rb protein. In addition, we have presented the latest Fas-induced signalling mechanism as a model for receptor-linked
caspase regulation. Finally, the structural and functional interactions of Ced-4 and its partial mam malian homologue, apoptosis
protease activating factor-1 (Apaf-1), are presented in a model which includes other Apafs. This model culminates in a caspase/Apaf
regulatory cascade to activate the executioners of programmed cell death following cytochrome c release from the mitochondria
of mammalian cells. The importance of these pathways in the treatment of disease is highly dependent on further characterization
of genes and other regulatory molecules in mammals.
Received 18 February 1998; accepted February 1998 相似文献
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G. Jackowski M. A. Heymann A. M. Rudolph E. Kun 《Cellular and molecular life sciences : CMLS》1982,38(9):1068-1069
Summary Aortic coarctation induces a large increase in poly ADP-R synthetase activity in non-cardiocyte nuclei, and in cardiocyte nuclei inhibition occures, suggesting a differentiation dependent regulation of polymer metabolism. In noncardiocyte nuclei DNA and poly ADP-R (polyadenosine diphosphoribose) synthesis exhibit positive correlation.Ackowledgment. This work was supported in part by the United States Air Force Office of Scientific Research (F-49620-81-C-007) and in part by a Program Project Grant of the United States Public Health Service (HL-24056). G. Jackowski is the recipient of a Postdoctoral Scholarship of the Canadian Heart Association and E. Kun is a Research Career Awardee of the United State Public Health Service. 相似文献
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Ling-Fei Zhang Shuai Jiang Mo-Fang Liu 《Cellular and molecular life sciences : CMLS》2017,74(16):2929-2941
The reprogramming of glucose metabolism from oxidative to glycolytic metabolism, known as the Warburg effect, is an anomalous characteristic of cancer cell metabolism. Recent studies have revealed a subset of microRNAs (miRNAs) that play critical roles in regulating the reprogramming of glucose metabolism in cancer cells. These miRNAs regulate cellular glucose metabolism by directly targeting multiple metabolic genes, including those encoding key glycolytic enzymes. In the first part of this review, we summarized the recent knowledge of miRNA regulation in the reprogramming of glucose metabolism in cancer cells and discussed the potential utilization of the key miRNA regulators as metabolic targets for developing new antitumor agents. Then, we summarized recent advances in methods and techniques for studying miRNA regulation in cancer cell metabolism. 相似文献