Prevention of tumorigenesis of oncogene-transformed rat fibroblasts with DNA site inhibitors of poly(ADP ribose) polymerase.

Tseng, Alexander M.; Lee, W M; Jakobovits, Edward B.; Kirsten, Eva; Hakam, Alaeddin; McLick, Jerome; Büki, Kálmán G.; Kun, Ernest

doi:10.1073/pnas.84.4.1107

Cited by 52 publications

(23 citation statements)

References 37 publications

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“…The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is a zinc ®nger nuclear protein which can bind both single-and double-stranded DNA breaks (Benjamin et al, 1980a,b). This enzyme, which depends on the presence of DNA strand breaks for its activity (Alvarez-Gonzalez et al, 1987), participates in a range of cellular processes which involve DNA repair (Hahn et al, 1973), DNA replication (SimbulanRosenthal et al, 1996), cell di erentiation (Bhatia et al, 1996), and tumor promotion (Tseng et al, 1987). PARP is a ubiquitous enzyme in nucleated eukaryotic cells (Ferro et al, 1984) which catalyzes the attachment of the ADP-ribose moiety of its speci®c substrate, NAD, to appropriate protein acceptors including, histones (Tanuma et al, 1985), topoisomerase I (Ferro et al, 1984), RNA polymerase II (Meisternst et al, 1997), DNA polymerase a (Yoshihara et al, 1985) and primarily the enzyme itself (Ikejima et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 prevents topoisomerase II inhibitor GL331-induced apoptosis is mediated by down-regulation of poly(ADP-ribose)polymerase activity

et al. 1998

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Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme responsible for DNA strand breaks, has been recently suggested to be crucial for apoptosis induced by a number chemotherapeutic drugs. In this study, we demonstrated that the PARP activity could be evidently elevated with a peak at 6 h when HL-60 cells were treated with a new anticancer drug GL331. Coincident with the peak of PARP activity, an apparent DNA fragmentation and apoptotic morphology were observed in cells treated with GL331. The subsequent apoptotic DNA fragmentation induced by GL331 could be completely blocked by transfecting cells with anti-sense PARP retroviral vector or by treating cells with PARP inhibitor, 3-aminobenzamide (3-AB). This blocking e ect thus suggests that activation of PARP was critically involved in GL331-induced apoptosis. The fact that Bcl-2 has been found to antagonize cell death induced by a wide variety of agents, accounts for why we examined whether if Bcl-2 could antagonize GL331 e ects. Interestingly, ectopic overexpression of Bcl-2 in either HL-60 or U937 cells caused in resistance towards GL331-elicited DNA fragmentation and cytotoxic e ect. Additionally, Bcl-2 also attenuated the poly(ADPribosyl)ation of PARP itself as well as Histone H1 at the early period of drug treatment. However, Bcl-2 did not in¯uence the extent of DNA strand breaks induced by GL331 in either control or Bcl-2-overexpressing cells. In addition, analysis of basal PARP activity in control and several Bcl-2 overexpressing clones revealed that Bcl-2 down-regulated PARP activity under the condition without DNA damages. Above ®ndings suggest that poly(ADP-ribosyl)ation of nuclear targets is important for apoptosis induced by DNA-reactive anticancer drugs.

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Section: Introductionmentioning

confidence: 99%

Bcl-2 prevents topoisomerase II inhibitor GL331-induced apoptosis is mediated by down-regulation of poly(ADP-ribose)polymerase activity

et al. 1998

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“…Trans-dominant inhibition of PARP sensitizes cells to DNA damaging agents, a ecting cell survival, apoptosis, cell cycle arrest and genomic stability (KuÈ pper et al, 1995;Schreiber et al, 1995). Roles for PARP in chromatin organization (Ding and Smulson, 1994), neoplastic transformation (Strain, 1985) and tumorigenesis (Tseng et al, 1987) have also been proposed.…”

Section: Introductionmentioning

confidence: 99%

Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase

Agarwal

Taylor

et al. 1997

Oncogene

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Poly-ADP-ribose polymerase (PARP) and p53 are both induced by DNA damage and each has been proposed to mediate the normal cellular response to damage. We ®nd that embryo ®broblasts from PARP-null mice have a *twofold lower basal level of p53 and that the induction of p53 in response to DNA damage or nucleotide depletion is more than twofold less than in normal mouse cells. These factors combine to decrease the induced level of the p53 protein in PARP-de®cient cells by 4 ± 5-fold, compared to normal cells. However, there is virtually no decrease in the induction of p53 activity in PARP-de®cient cells, as assayed with a p53-responsive promoter. Furthermore, cells lacking PARP arrest normally in G 1 after DNA damage, in contrast to cells lacking p53, where this checkpoint is absent. Other p53-dependent properties, such as the mitotic spindle checkpoint and permissivity for gene ampli®cation, are also normal in PARP-de®cient cells. We conclude that the induced level of the p53 protein is governed by a combination of PARP-dependent and PARP-independent pathways and that the activation of p53 is largely PARP-independent. The results are consistent with a model in which the regulation of gene expression by p53 involves both increases in the amount of the protein and activation of p53 as a transcription factor.

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“…The involvement of ADPRT in cell proliferation is supported by the observation that expression of ADPRT is induced when cells are stimulated to proliferate (Menegazzi et al 1988;McNerney et al 1989;Cesarone et al 1990). With respect to neoplastic transformation, inhibitors of ADPRT can prevent oncogenic transformation of cultured cells (Tseng et al 1987;Nakagawa et al 1988); however, ADPRT activity has also been inversely correlated with transformation (Strain 1985;Yamagami et al 1985;Miller et al 1989). ADPRT is also implicated in cytotoxicity, because activation of ADPRT causes intracellular NAD + depletion and thereby energy depletion, which leads to cell death (Berger 1985;Gaal et al 1987).…”

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Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

Wang¹,

Auer²,

Stingl³

et al. 1995

Genes Dev.

741

504

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Poly(ADP-ribosyl)ation is catalyzed by NAD + :protein(ADP-ribosyl)transferase (ADPRT), a chromatinassociated enzyme which, in the presence of DNA breaks, transfers ADP-ribose from NAD + to nuclear proteins. This post-translational modification has been implicated in many fundamental processes, like DNA repair, chromatin stability, cell proliferation, and cell death. To elucidate the biological function of ADPRT and poly(ADP-ribosyl)ation in vivo the gene was inactivated in the mouse germ line. Mice homozygous for the ADPRT mutation are healthy and fertile. Analysis of mutant tissues and fibroblasts isolated from mutant fetuses revealed the absence of ADPRT enzymatic activity and poly(ADP-ribose), implying that no poly(ADP-ribosyl)ated proteins are present. Mutant embryonic fibroblasts were able to efficiently repair DNA damaged by UV and alkylating agents. However, proliferation of mutant primary fibroblasts as well as thymocytes following y-radiation in vivo was impaired. Moreover, mutant mice are susceptible to the spontaneous development of skin disease as -30% of older mice develop epidermal hyperplasia. The generation of viable ADPRT-/-mice negates an essential role for this enzyme in normal chromatin function, but the impaired proliferation and the onset of skin lesions in older mice suggest a function for ADPRT in response to environmental stress.

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Prevention of tumorigenesis of oncogene-transformed rat fibroblasts with DNA site inhibitors of poly(ADP ribose) polymerase.

Cited by 52 publications

References 37 publications

Bcl-2 prevents topoisomerase II inhibitor GL331-induced apoptosis is mediated by down-regulation of poly(ADP-ribose)polymerase activity

Bcl-2 prevents topoisomerase II inhibitor GL331-induced apoptosis is mediated by down-regulation of poly(ADP-ribose)polymerase activity

Defective induction but normal activation and function of p53 in mouse cells lacking poly-ADP-ribose polymerase

Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

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