A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress

Huang, Qing; Yt, Wu; Hl, Tan; Ong, Choon Nam; Shen, Huifeng

doi:10.1038/cdd.2008.151

Cited by 106 publications

(100 citation statements)

References 46 publications

(68 reference statements)

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“…In addition to mediating BER by recruiting BER intermediates like ␤-pol, poly(ADP-ribose) polymerases are the key regulators of cell survival and death (34). Huang et al (35) in their study utilizing Bax ϩ/Ϫ Bak Ϫ/Ϫ mouse embryonic fibroblasts, show depletion in ATP secondary to poly-(ADP-ribose) polymerase-1 activation, which in turn inhibits Frap1, a mediator of cellular response to DNA damage. We suggest that down-regulation in expression of key enzymes in the BER pathway renders available poly(ADP-ribose) polymerases futile and are thus cleaved by Casp3 triggering apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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Aging and DNA polymerase ␤ deficiency (␤-pol ؉/؊ ) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load in mice. Folate deficiency (FD) has been shown to induce DNA damage repaired via the base excision repair (BER) pathway. We anticipated that FD and BER deficiency would interact to accelerate aberrant crypt foci (ACF) formation and tumor development in ␤-pol haploinsufficient animals. FD resulted in a significant increase in ACF formation in wild type (WT) animals exposed to 1,2-dimethylhydrazine, a known colon and liver carcinogen; however, FD reduced development of ACF in ␤-pol haploinsufficient mice. Prolonged feeding of the FD diet resulted in advanced ACF formation and liver tumors in wild type mice. However, FD attenuated onset and progression of ACF and prevented liver tumorigenesis in ␤-pol haploinsufficient mice, i.e. FD provided protection against tumorigenesis in a BER-deficient environment in all tissues where 1,2-dimethylhydrazine exerts its damage. Here we show a distinct down-regulation in DNA repair pathways, e.g. BER, nucleotide excision repair, and mismatch repair, and decline in cell proliferation, as well as an up-regulation in poly(ADP-ribose) polymerase, proapoptotic genes, and apoptosis in colons of FD ␤-pol haploinsufficient mice.Folate deficiency is an important public health concern because of the role folate plays in the development of many different health problems, including neural tube defects, cardiovascular disease, Alzheimer disease, and cancer, specifically colon cancer. It has been proposed that the carcinogenic properties of folate deficiency may be related to a decrease in DNA methylation, perhaps as a function of reduced S-adenosylmethionine levels, an increase in the uracil content of DNA, or an increase in oxidative stress by alterations in thiol switches. Folate deficiency has also been shown to increase (in cells, animal models, and humans) levels of single strand breaks (1-5), micronucleus formation (6, 7), chromosomal aberration (8, 9), and mutation frequency (10, 11), all potentially downstream effects of high levels of uracil in DNA and oxidative damage to DNA.The DNA repair pathway for removal of uracil and oxidized bases is the base excision repair (BER) 2 pathway. The BER pathway is believed to repair small, non-helix-distorting lesions in the DNA. It has been estimated to be responsible for the repair of as many as one million nucleotides per cell per day (12), stressing its importance in the maintenance of genomic stability. It has been suggested that BER has evolved in response to in vivo exposure of DNA to reactive oxygen species and endogenous alkylation, and that this pathway suppresses spontaneous mutagenesis (13). In the initial elucidation of the BER pathway the following steps were involved: (i) removal of the damaged base by a DNA glycosylase; (ii) incision of the phosphate backbone by an endonuclease; (iii) synthesis of new DNA by a polymerase; (iv) excision of the deoxyribose phosphate moie...

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Section: Discussionmentioning

confidence: 99%

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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“…2). 90 Together, these studies indicate that under conditions of cellular stress or after engagement of death receptor signaling, ROS act as positive regulators of autophagy, whereas autophagy stimulation in turn can either dampen ROS production (by removing mitochondria) or increase oxidative stress (by removing catalase). The functional effects of ROS-mediated autophagy on cell death appear to be dictated by the type of stress (e.g., cytoprotective after amino acid starvation, proapoptotic after TNF-engagement), the amount and the location of the prevailing type of ROS produced.…”

Section: Redox-regulation Of Autophagy Pathwaysmentioning

confidence: 99%

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Dewaele¹,

Maes²,

Agostinis³

2010

Autophagy

276

199

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“…AMPK is activated by phosphorylation at threonine 172 in the catalytic ␣ subunit (19) in a constitutive fashion by the upstream kinase LKB1; however, this phosphorylation is rapidly removed by a phosphatase to maintain low basal activity (18,43). AMPK is activated under conditions that decrease cellular ATP levels, such as hypoxia, DNA damage, glucose deprivation, and free radical generation (2,24,32,42). This includes nitric oxideinduced activation of AMPK (2).…”

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confidence: 99%

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

Meares

Hughes

Naatz

et al. 2011

Molecular and Cellular Biology

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While there can be detrimental consequences of nitric oxide production at pathological concentrations, eukaryotic cells have evolved protective mechanisms to defend themselves against this damage. The unfoldedprotein response (UPR), activated by misfolded proteins and oxidative stress, is one adaptive mechanism that is employed to protect cells from stress. Nitric oxide is a potent activator of AMP-activated protein kinase (AMPK), and AMPK participates in the cellular defense against nitric oxide-mediated damage in pancreatic ␤-cells. In this study, the mechanism of AMPK activation by nitric oxide was explored. The known AMPK kinases LKB1, CaMKK, and TAK1 are not required for the activation of AMPK by nitric oxide. Instead, this activation is dependent on the endoplasmic reticulum (ER) stress-activated protein IRE1. Nitric oxide-induced AMPK phosphorylation and subsequent signaling to AMPK substrates, including Raptor, acetyl coenzyme A carboxylase, and PGC-1␣, is attenuated in IRE1␣-deficient cells. The endoribonuclease activity of IRE1 appears to be required for AMPK activation in response to nitric oxide. In addition to nitric oxide, stimulation of IRE1 endoribonuclease activity with the flavonol quercetin leads to IRE1-dependent AMPK activation. These findings indicate that the RNase activity of IRE1 participates in AMPK activation and subsequent signaling through multiple AMPK-dependent pathways in response to nitrosative stress.Nitric oxide, an important mediator of both physiological and pathological processes, has been implicated in the development of a number of inflammatory diseases. When produced at low concentrations, nitric oxide can promote cell growth and survival. At high concentrations, such as those produced during inflammation by inducible nitric oxide synthase (iNOS), nitric oxide induces extensive cellular injury that includes DNA damage, inhibition of oxidative metabolism, and induction of endoplasmic reticulum (ER) stress (5, 12, 39). Pancreatic ␤-cells are exquisitely sensitive to oxidative damage, as glucose-stimulated insulin secretion requires the oxidation of glucose to CO 2 , resulting in the accumulation of ATP. Nitric oxide, produced in micromolar concentrations in response to interleukin 1 (IL-1) and gamma interferon (IFN-␥), mediates the damaging effects of these cytokines on ␤-cell function (3, 33). While nitric oxide stimulates cellular damage, it also activates a number of signaling pathways that limit additional cellular damage and repair existing damage. In pancreatic ␤-cells, the protective responses activated by nitric oxide include (i) JNK-dependent induction of GADD45␣ (growth arrest and DNA damage-inducible protein 45␣) and DNA repair, (ii) activation of AMP-activated protein kinase (AMPK), resulting in enhanced metabolic recovery, and (iii) activation of the unfolded-protein response (UPR) (25,34,38,54,57,61).AMPK is a conserved heterotrimeric (␣, ␤, and ␥ subunits) serine/threonine kinase involved in sensing and responding to the energetic demand within eukaryotic cel...

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A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress

Cited by 106 publications

References 46 publications

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

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