p53-dependent apoptosis or growth arrest induced by different forms of radiation in U2OS cells: p21WAF1/CIP1 repression in UV induced apoptosis

Allan, Lindsey A.; Fried, Mike

doi:10.1038/sj.onc.1202931

Cited by 71 publications

(71 citation statements)

References 56 publications

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“…25 The different cellular responses of drug-treated U2-OS cells are reminiscent of those observed in the same cell line following genotoxic damage induced by different forms of radiation. 15 The latter study does not provide an explanation of the dual function of p53 in response to different types of genotoxic stress. On the basis of the findings of our study, it is tempting to speculate that the initiation of apoptosis is related to a differential recognition of specific DNA lesions resulting in different signaling processes.…”

Section: Control Loading Is Shown By Actinmentioning

confidence: 84%

“…The study was performed in a human osteosarcoma cell line (U2-OS) carrying a wild-type p53 gene and known to undergo p53-dependent apoptosis or growth arrest induced by different types of radiation. 15 The results indicated that, in contrast to cisplatin which induced an apoptotic response, the treatment with the multinuclear complex resulted in cell cycle arrest and cytostasis. Cisplatin-induced apoptosis was associated with a marked induction of p53 expression and phosphorylation of Ser15.…”

Section: Introductionmentioning

confidence: 99%

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Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

et al. 2002

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Mononuclear and multinuclear platinum complexes are known to induce distinct types of DNA lesions and exhibit different profiles of antitumor activity, in relation to p53 mutational status. In this study, we investigated the cellular effects of exposure to two platinum compounds (cisplatin and the multinuclear platinum complex BBR 3464), in the osteosarcoma cell line, U2-OS, carrying the wild-type p53 gene and capable of undergoing apoptosis or cell cycle arrest in response to diverse genotoxic stresses. In spite of the ability of both compounds to up-regulate p53 at cytotoxic concentrations, exposure to BBR 3464 resulted in cell cycle arrest but only cisplatin was capable of inducing significant levels of apoptosis and phosphorylation at the Ser15 residue of p53. The cisplatin-induced protein phosphorylation, not detectable in cells treated with BBR 3464, was associated with RPA phosphorylation, a specific up-regulation of Bax and downregulation of p21 WAF1 . Cells treated with BBR 3464 displayed a different cellular response with evidence of cytostasis associated with a high induction of p21 WAF1 . The regulation of p21 WAF1 after cisplatin or BBR 3464 exposure required a p53 signal, as documented using stable transfectants expressing a dominant-negative form of p53 (175 his ). Taken together, these results indicate that cellular response to different genotoxic lesions (i.e. apoptosis or growth arrest) is associated with a specific recognition of DNA damage and a different p53-mediated signaling pathway. Multinuclear platinum complexes could be regarded as useful tools for investigating the p53-mediated process of cell cycle arrest in response to DNA damage.

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Section: Control Loading Is Shown By Actinmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

et al. 2002

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“…Cells were then allowed to grow for one (SK-MEL-28) or 2 weeks (C8146A, UACC-2571, LOX-MM, and UACC-62). For treatments of C8146A cells with the p53 reversible inhibitor pifithrin-␣ (Calbiochem), cells were treated with 20 M pifithrin-␣ 4 h prior to UV treatment, as previously described (40). Pifithrin-␣ is a small water-soluble p53 inhibitor that was isolated in 1999 (41).…”

Section: Methodsmentioning

confidence: 99%

“…4 h after UV exposure (14 J/m 2 ), siRNA-transfected cells were lysed in buffer containing 500 mM Tris-HCl (pH 9.0), 20 mM EDTA (pH 8.0), 10 mM NaCl, 1% SDS, 1 mg/ml Proteinase K, and incubated at 50°C for 24 h. The 4-h time point after UV treatment was chosen to minimize p53-independent apoptotic effects that arise at later time points as was observed for fibroblasts (50,51), A549 cells (52), and U2OS cells (40). DNA was purified from the cell extract via phenol extraction/isopropanol precipitation, re-suspended in H 2 O, digested with RNase A, loaded onto a 1.5% agarose gel, and stained with ethidium bromide.…”

Section: Methodsmentioning

confidence: 99%

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

Lin

Yang

Wilder

et al. 2010

Journal of Biological Chemistry

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The S100B-p53 protein complex was discovered in C8146A malignant melanoma, but the consequences of this interaction required further study. When S100B expression was inhibited in C8146As by siRNA (siRNA S100B ), wt p53 mRNA levels were unchanged, but p53 protein, phosphorylated p53, and p53 gene products (i.e. p21 and PIDD) were increased. siRNA S100B transfections also restored p53-dependent apoptosis in C8146As as judged by poly(ADP-ribose) polymerase cleavage, DNA ladder formation, caspase 3 and 8 activation, and aggregation of the Fas death receptor (؉UV); whereas, siRNA S100B had no effect in SK-MEL-28 cells containing elevated S100B and inactive p53 (p53R145L mutant). siRNA S100B -mediated apoptosis was independent of the mitochondria, because no changes were observed in mitochondrial membrane potential, cytochrome c release, caspase 9 activation, or ratios of pro-and anti-apoptotic proteins (BAX, Bcl-2, and Bcl-X L ). As expected, cells lacking S100B (LOX-IM VI) were not affected by siRNA S100B , and introduction of S100B reduced their UV-induced apoptosis activity by 7-fold, further demonstrating that S100B inhibits apoptosis activities in p53-containing cells. In other wild-type p53 cells (i.e. C8146A, UACC-2571, and UACC-62), S100B was found to contribute to cell survival after UV treatment, and for C8146As, the decrease in survival after siRNA S100B transfection (؉UV) could be reversed by the p53 inhibitor, pifithrin-␣. In summary, reducing S100B expression with siRNA was sufficient to activate p53, its transcriptional activation activities, and p53-dependent apoptosis pathway(s) in melanoma involving the Fas death receptor and perhaps PIDD. Thus, a well known marker for malignant melanoma, S100B, likely contributes to cancer progression by down-regulating the tumor suppressor protein, p53.In addition to regulating numerous genes and pathways involved in cell cycle control (1), the tumor suppressor protein, p53, is an important component for inducing apoptosis (2-4). The p53 protein activates the transcription of pro-apoptotic factors (BAX, Bak, Fas/APO-1, PIDD, etc.) as well as suppresses the transcription of anti-apoptotic genes (Bcl-2, Bcl-X L , etc.) (5, 6). In addition, p53 itself up-regulates apoptosis, without transcription activation, by directly localizing to mitochondria following DNA damage and interacting with anti-apoptotic proteins such as Bcl-X L to free pro-apoptotic proteins like BAX (2, 3, 5, 7). Under stress, the p53 protein can also contribute to apoptosis by facilitating the transport of death receptors such as Fas/APO-1 and/or Killer/DR5 from cytoplasmic stores to the cell surface as required for programmed cell death (5, 8). Although, it is now clear that p53-dependent pathways of apoptosis are numerous and are regulated in a cell-type and signalspecific manner (5).Apoptosis is initiated by a variety of stimuli, including withdrawal of growth factors, activation of specific receptors, such as Fas antigen and TNF receptor, and/or by exposure to UV radiation, ␥ irradiation, DNA-da...

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“…Although DNA damageinduced apoptosis typically also depends on p53, p53 target genes other than p21 are involved (Yu and Zhang, 2005). Thus, p21 has an antiapoptotic function (Polyak et al, 1996;Janicke et al, 2007) and is actively repressed in apoptotic cells (Allan and Fried, 1999;Seoane et al, 2002). Both, DNA damage-induced apoptosis and senescence are considered to be important physiological mechanisms to withdraw pre-neoplastic cells from proliferation (Halazonetis et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

2010

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The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cellcycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.

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p53-dependent apoptosis or growth arrest induced by different forms of radiation in U2OS cells: p21WAF1/CIP1 repression in UV induced apoptosis

Cited by 71 publications

References 56 publications

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

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