Roles of poly(ADP-ribosyl)ation and PARP in apoptosis, DNA repair, genomic stability and functions of p53 and E2F-1

Smulson, Mark E.; Simbulan-Rosenthal, Cynthia M.; Boulares, A. Hamid; Yakovlev, Alexander G.; Stoica, Bogdan A.; Iyer, Sudha; Luo, Ruibai; Haddad, B; Wang, Z.Q; Pang, Te Ling; Jung, Mira; Dritschilo, Anatoly; Rosenthal, Dean S.

doi:10.1016/s0065-2571(99)00024-2

Cited by 113 publications

(87 citation statements)

References 71 publications

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“…For MIP-1␤, the percent inhibition of chemokine release from the controls was 43,45, and 55% at 6 h; 48, 47, and 61% at 18 h; and 13, 23, and 54% at 24 h for 15, 20, and 25 M curcumin, respectively. Similarly, for MIP-1␣ the percent inhibition over control values was 38,39, and 53% at 6 h; 29,31, and 49% at 18 h; and 18, 31, and 44% at 24 h for 15, 20, and 25 M curcumin, respectively. These data show that curcumin rapidly inhibits chemokine production induced by IPP in ␥␦ T cells, but that at low doses (Ͻ15 M) some recovery from the inhibitory effects of curcumin occurs over time.…”

Section: Resultsmentioning

confidence: 86%

“…Once activated, caspases initiate a cascade of proteolysis that involves further processing/activation of additional caspases, and ultimately cleavage of specific cellular proteins, such as PARP, an enzyme involved in DNA repair, leading to its inactivation (29). Assessment of immunoreactivity for the cleaved form of PARP (p85 fragment) indicated that this was also increased in cells treated with 30 g/ml IPP2X, 30 M curcumin, and IPP2X plus curcumin for 8 h (Fig.…”

Section: Resultsmentioning

confidence: 94%

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Curcumin Inhibits Activation of Vγ9Vδ2 T Cells by Phosphoantigens and Induces Apoptosis Involving Apoptosis-Inducing Factor and Large Scale DNA Fragmentation

Cipriani

Borsellino

Knowles

et al. 2001

The Journal of Immunology

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Curcumin, in addition to its role as a spice, has been used for centuries to treat inflammatory disorders. Although the mechanism of action remains unclear, it has been shown to inhibit the activation of NF-κB and AP-1, transcription factors required for induction of many proinflammatory mediators. Due to its low toxicity it is currently under consideration as a broad anti-inflammatory, anti-tumor cell agent. In this study we investigated whether curcumin inhibited the response of γδ T cells to protease-resistant phosphorylated derivatives found in the cell wall of many pathogens. The results showed that curcumin levels ≥30 μM profoundly inhibited isopentenyl pyrophosphate-induced release of the chemokines macrophage inflammatory protein-1α and -1β and RANTES. Curcumin also blocked isopentenyl pyrophosphate-induced activation of NF-κB and AP-1. Commencing around 16 h, treatment with curcumin lead to the induction of cell death that could not be reversed by APC, IL-15, or IL-2. This cytotoxicity was associated with increased annexin V reactivity, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the nucleus, and morphological evidence of nuclear disintegration. However, curcumin led to only large scale DNA chromatolysis, as determined by a combination of TUNEL staining and pulse-field and agarose gel electrophoresis, suggesting a predominantly apoptosis-inducing factor-mediated cell death process. We conclude that γδ T cells activated by these ubiquitous Ags are highly sensitive to curcumin, and that this effect may contribute to the anti-inflammatory properties of this compound.

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 94%

Curcumin Inhibits Activation of Vγ9Vδ2 T Cells by Phosphoantigens and Induces Apoptosis Involving Apoptosis-Inducing Factor and Large Scale DNA Fragmentation

Cipriani

Borsellino

Knowles

et al. 2001

The Journal of Immunology

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“…One possibility is covalent poly(ADP-ribosyl)ation of p53. Poly(ADPribosyl)ation of p53 has been observed in vivo in osteosarcoma cells undergoing spontaneous apoptosis (17,49). To date there has been no report of poly(ADP-ribosyl)ation of p53 following DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) Polymerase-1 Is a Positive Regulator of the p53-mediated G1 Arrest Response following Ionizing Radiation

Wieler

Gagné²,

Vaziri

et al. 2003

Journal of Biological Chemistry

102

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The p53 tumor suppressor protein plays a critical role in the cellular response to DNA damage leading to cell cycle arrest or apoptosis depending on cell type, culture conditions, and the extent of DNA damage. Loss of the p53-dependent DNA damage response can lead to genomic instability and the survival of cells carrying mutations and carcinogenic lesions thereby contributing to malignancy (1). DNA strand breaks produced by ionizing radiation (IR) 1 or by DNA repair intermediates following treatment with UV radiation or chemotherapeutic agents result in the accumulation of p53 protein and in the activation of its transcriptional activity (reviewed in Refs. 2 and 3). Elevated levels of p53 protein are believed to be important to initiate the events that lead to G 1 arrest or apoptosis after DNA damage. There is compelling evidence that post-translational modification of p53 is required for its stabilization, as well as for activation of its latent sequence-specific DNA-binding and transactivation functions. Once p53 becomes activated it binds as a tetramer to p53 responsive elements on double stranded DNA consisting of two half-sites (5Ј-PuPuPuC(A/T)(T/A)GPyPyPy-3Ј) separated by a spacer consisting of 0 -13 nucleotides (4). The site-specific DNA-binding activity of p53 leads to transcriptional activation of p53 target genes. Covalent modification of p53 has also been shown to regulate its subcellular localization, tetramerization, interaction with other proteins, and degradation. p53 protein is modified in vivo through phosphorylation, acetylation, poly(ADP-ribosyl)ation, ubiquitination, and sumoylation reactions (reviewed in Refs. 2 and 5).The events upstream of p53 activation are complex and not well understood. Several DNA damage sensory molecules are believed to relay the DNA damage signal to p53; each may be involved in the response to one or more types of DNA damage. For example, ataxia-telangiectasia-mutated kinase protein is involved in the activation of p53 in response to IR (6, 7), and ataxia telangiectasia-related kinase protein is involved in the activation of p53 in response to UV irradiation (8).Poly(ADP-ribose) polymerase (PARP-1) is an abundant nuclear enzyme that binds to, and is activated by, DNA single and double strand breaks (reviewed in Refs. 9 -11). Its activation represents one of the earliest responses to DNA damage in the cell. PARP-1 catalyzes the sequential transfer of ADP-ribose monomers onto nuclear protein acceptors using NAD ϩ as substrate. During the process of poly(ADP-ribosyl)ation, NAD ϩ is hydrolyzed and released as free nicotinamide. More than 30 nuclear proteins have been identified as poly(ADP-ribose) (pADPr) acceptors, with PARP-1 itself being the major target, via its automodification domain. pADPr acceptor proteins may be modified through covalent as well as through non-covalent association with pADPr, either free or bound to PARP-1. Poly-(ADP-ribose) glycohydrolase is the major enzyme responsible for the hydrolysis of pADPr. There is general agreement, based on genetic ...

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“…It is clear that this short-lived post-translational modification plays an important, although incompletely defined, role in DNA damage response and apoptosis (33,34). PARP-1 enzymatic activity is dependent upon binding to DNA strand breaks and is rapidly activated in response to cellular stresses, such as heat shock, gamma radiation, exposure to carcinogens, and treatment with chemotherapy agents.…”

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confidence: 99%

Apoptosis in Leukemia Cells Is Accompanied by Alterations in the Levels and Localization of Nucleolin

Thomas

et al. 2003

Journal of Biological Chemistry

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Molecular defects in apoptotic pathways are thought to often contribute to the abnormal expansion of malignant cells and their resistance to chemotherapy. Therefore, a comprehensive knowledge of the mechanisms controlling induction of apoptosis and subsequent cellular disintegration could result in improved methods for prognosis and treatment of cancer. In this study, we have examined apoptosis-induced alterations in two proteins, nucleolin and poly(ADP-ribose) polymerase-1 (PARP-1), in U937 leukemia cells. Nucleolin is expressed at high levels in malignant cells, and it is a multifunctional and mobile protein that can shuttle among the nucleolus, nucleoplasm, cytoplasm, and plasma membrane. Here, we report our findings that UV irradiation or camptothecin treatment of U937 cells induced apoptosis and caused a significant change in the levels and localization of nucleolin within the nucleus. Additionally, nucleolin levels were dramatically decreased in extracts containing the cytoplasm and plasma membrane. These alterations could be abrogated by pre-incubation with an inhibitor of PARP-1 (3-aminobenzamide), and our data support a potential role for nucleolin in removing cleaved PARP-1 from dying cells. Furthermore, both nucleolin and cleaved PARP-1 were detected in the culture medium of cells undergoing apoptosis, associated with particles of a size consistent with apoptotic bodies. These results indicate that nucleolin plays an important role in apoptosis, and could be a useful marker for assessing apoptosis or detecting apoptotic bodies. In addition, the data provide a possible explanation for the appearance of nucleolin and PARP-1 autoantibodies in some autoimmune diseases.

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Roles of poly(ADP-ribosyl)ation and PARP in apoptosis, DNA repair, genomic stability and functions of p53 and E2F-1

Cited by 113 publications

References 71 publications

Curcumin Inhibits Activation of Vγ9Vδ2 T Cells by Phosphoantigens and Induces Apoptosis Involving Apoptosis-Inducing Factor and Large Scale DNA Fragmentation

Curcumin Inhibits Activation of Vγ9Vδ2 T Cells by Phosphoantigens and Induces Apoptosis Involving Apoptosis-Inducing Factor and Large Scale DNA Fragmentation

Poly(ADP-ribose) Polymerase-1 Is a Positive Regulator of the p53-mediated G1 Arrest Response following Ionizing Radiation

Apoptosis in Leukemia Cells Is Accompanied by Alterations in the Levels and Localization of Nucleolin

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