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

Agarwal, Munna L.; Agarwal, Archana; Taylor, William R.; Wang, Zhao Qi; Wagner, Erwin F.; Stark, George R.

doi:10.1038/sj.onc.1201274

Cited by 85 publications

(40 citation statements)

References 36 publications

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“…Similar data were also obtained from another human glioblastoma cell line, U87MG cells, with wtp53 status (Figure 2d). These results were consistent with previous observations using V79-derivative PARP-de®cient or PARP-null cells (Whitacre et al, 1995;Agarwal et al, 1997). These results suggested that PARP is not essential for DNA damageinduced p53 accumulation but is required for an intact p53 response after DNA damage including rapid and higher magnitude of p53 accumulation.…”

Section: Discussionsupporting

confidence: 83%

“…The results of Northern blotting analysis supported this suggestion (Figure 3). The 10 h delay of WAF1 expression and its appearance at 24 h after irradiation in 3AB-treated U87MG cells (Figure 2d) recapitulated the observation with PARP-null MEFs, although the 12 h delay in adriamycin-induced WAF1 expression was suggested not to be signi®cant in a previous report (Agarwal et al, 1997). Further evidence for the involvement of PARP in regulation of p53 function was provided by the results of gel mobility shift assay.…”

Section: Discussionsupporting

confidence: 47%

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Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation

et al. 1998

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p53 and poly(ADP-ribose) polymerase (PARP) are both DNA damage recognition proteins and can be functionally activated by DNA strand breaks. To understand the functional interaction between these two proteins, the eects of a PARP inhibitor, 3-aminobenzamide (3AB), on the p53 pathway were investigated in human glioblastoma cells with dierent p53 status. Consistent with previous studies, irradiation with g-rays induced both p53 and WAF1 accumulation in A-172 cells (wtp53) but not in T98G cells (mp53). However, the presence of 3AB but not its analog suppressed radiation-induced accumulation of wtp53 and the expression of WAF1 and MDM2. Similar results were also obtained from U87MG, another human glioblastoma cell line with wtp53 status. Northern blotting analysis showed that 3AB inhibited the g-ray-induced WAF1 gene expression. Moreover, 3AB but not its analog inhibited irradiationinduced activation of sequence-speci®c DNA binding of wtp53 as detected using 32 P-labeled or biotin-labeled p53 consensus sequence (p53CON). However, immunoblotting with an anti-poly(ADP-ribose) antibody showed that p53 proteins of the p53CON-bound fraction did not contain poly(ADP-ribose) (PAR). These ®ndings suggested that poly(ADP-ribosyl)ation is required for rapid accumulation of p53, activation of p53 sequence-speci®c DNA binding and its transcriptional activity after DNA damage.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 47%

Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation

et al. 1998

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“…All transfections into WiT49 and HCT116 cells were done using LipofectAMINE Plus (Invitrogen). The p53-dependent reporter construct pConALuc (19) and PODXL promoter-reporter constructs (18) were cotransfected with pRLTK (Promega). The indicated amount of CP-31398, an equivalent volume of Me 2 SO solvent, or doxorubicin (200 ng/ml) was added 24 h post-transfection, and cells were harvested 19 h later.…”

Section: Methodsmentioning

confidence: 99%

The Wilms Tumor Suppressor-1 Target Gene Podocalyxin Is Transcriptionally Repressed by p53

Stanhope-Baker¹,

Kessler²,

et al. 2004

Journal of Biological Chemistry

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Wilms tumor is a pediatric kidney cancer that affects 1 in 10,000 children. The Wilms tumor suppressor-1 (WT1) 1 gene was identified as a tumor suppressor gene based upon the presence of WT1 mutations in a subset (ϳ10 -15%) of Wilms tumor samples (reviewed in Ref. 1). However, the majority of Wilms tumor cases cannot be explained by genetic alteration of the WT1 locus. There may be disruption of biological pathways either upstream or downstream of WT1, or there may be pathways independent of WT1 leading to this type of neoplasm. Several lines of evidence suggest that p53 also plays an important role in the development and/or progression of Wilms tumors. The p53 and WT1 tumor suppressor genes encode transcription factors that have been shown to interact physically and to modulate each other's function in some experimental situations (2). p53 can alter the transcription regulatory activity of WT1. In addition, WT1 stabilizes the p53 protein, alters its activity as a transcription factor, and prevents p53-induced apoptosis (2, 3). Physical and functional interaction has also been observed between the p53 family members p73 and p63 and WT1 (4). Further evidence for biologically relevant interaction between WT1 and p53 includes the fact that the majority of Wilms tumors develop in the presence of wild-type p53 (5). This is in contrast to adult onset human tumors, in which p53 mutations are frequently observed (ϳ50%). The small subset of Wilms tumors that do harbor p53 mutations develop into much more aggressive anaplastic tumors (between 3 and 7% of the total) that are characterized by unfavorable histology, increased metastasis, chemoresistance, and poor prognosis (6 -9). Moreover, Li-Fraumeni patients carrying germ-line p53 mutations are predisposed to development of Wilms tumors (10), and Wilms tumors are one of a small number of cancers that are specifically associated with such mutations (11). To better understand the involvement of both p53 and WT1 in pathways leading to Wilms tumorigenesis, we have used cDNA microarrays to profile gene expression changes dependent upon the activity of these two factors.To accomplish this, we developed strategies to alter the function of WT1 and p53 in a Wilms tumor cell line, WiT49. This cell line is characteristic of anaplastic Wilms tumors in that it expresses wild-type WT1 and mutant p53. We have previously shown that WT1 activity can be effectively abrogated in WiT49 cells by expression of a naturally occurring dominant-negative mutant version of the protein (DDS5) (12). To restore wild-type p53 function in WiT49 cells, we made use of the small molecule compound CP-31398 developed by Pfizer. CP-31398 was originally shown to stabilize the p53 protein with mutation at codon 173, 175, 249, or 273 in the wild-type conformation and to allow its transcriptional and tumor suppressor functions (13). More recently, it has been shown that CP-31398 can stabilize the wild-type p53 protein as well (14 -16). We found here that CP-31398 restores activity to the codon 248 mutant p53 prese...

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“…Homozygous or heterozygous inactivation of p53 in mice or heterozygous inactivation in humans predisposes to neoplasia, and mutation of p53 occurs in over half of all spontaneous human tumors (Donehower et al, 1992;Li and Fraumeni, 1969;Srivastava et al, 1990;Greenblatt et al, 1994). In response to DNA damage, p53 is stabilized and activated to bind to speci®c DNA sequences, where it drives the transcription of genes involved in cell cycle arrest and apoptosis (Fritsche et al, 1993;Hupp et al, 1995;El-Deiry et al, 1993;Dulic et al, 1994;Miyashita and Reed, 1995;Attardi et al, 1996;Agarwal et al, 1997). p53 is also activated in response to stimuli that do not generate broken DNA directly, including nucleotide deprivation and hypoxia (Linke et al, 1996;Graeber et al, 1996;Agarwal et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In response to DNA damage, p53 is stabilized and activated to bind to speci®c DNA sequences, where it drives the transcription of genes involved in cell cycle arrest and apoptosis (Fritsche et al, 1993;Hupp et al, 1995;El-Deiry et al, 1993;Dulic et al, 1994;Miyashita and Reed, 1995;Attardi et al, 1996;Agarwal et al, 1997). p53 is also activated in response to stimuli that do not generate broken DNA directly, including nucleotide deprivation and hypoxia (Linke et al, 1996;Graeber et al, 1996;Agarwal et al, 1997). The cell cycle is regulated at several points by p53, which is required to inhibit entry into S phase in response to either DNA damage or the arrest caused by inhibitors of microtubule assembly, and the latter function links the loss of p53 to aneuploidy (Kastan et al, 1991;Dulic et al, 1994;Cross et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

p53 inhibits entry into mitosis when DNA synthesis is blocked

Taylor

Agarwal

et al. 1999

Oncogene

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Human and mouse ®broblasts with normal p53 fail to enter mitosis when DNA synthesis is blocked by aphidicolin or hydroxyurea. Isogenic p53-null ®broblasts do enter mitosis with incompletely replicated DNA, revealing that p53 contributes to a checkpoint that ensures that mitosis does not occur until DNA synthesis is complete. When treated with N-(phosphonacetyl)-Laspartate (PALA), which inhibits pyrimidine nucleotide synthesis, leading to synthesis of damaged DNA from highly unbalanced dNTP pools, p53-null cells enter mitosis after they have completed DNA replication, but cells with wild-type p53 do not, revealing that p53 also mediates a checkpoint that monitors the quality of newly replicated DNA.

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

Cited by 85 publications

References 36 publications

Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation

Poly(ADP-ribosyl)ation is required for p53-dependent signal transduction induced by radiation

The Wilms Tumor Suppressor-1 Target Gene Podocalyxin Is Transcriptionally Repressed by p53

p53 inhibits entry into mitosis when DNA synthesis is blocked

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