Wild-type function of the p53 tumor suppressor protein is not required for apoptosis of mouse hepatoma cells

Unger, Christina; Buchmann, Albrecht; Bünemann, Christoph L; Kress, Stefan; Schwarz, Michael

doi:10.1038/sj.cdd.4400321

Cited by 21 publications

(17 citation statements)

References 31 publications

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“…By contrast, there was a tendency for an increase rather than a decrease in p53 mRNA in UV-exposed 55.1c cells, but the effect was not statistically significant (n 5 4, data not shown). Both 70.4 and 55.1c cells are very similarly triggered into apoptosis by UV-irradiation 9 and this effect was also observed under the conditions used in the present series of experiments 24 hr post irradiation. Induction of apoptosis was, among others, indicated by a strong increase in the activity of the executor caspase 3, which is activated in the so- did not lead to a any significant diminution of p53 mRNA, while a decrease in P53 protein was already detected after 1-2 hr in the H 2 O 2 -exposed cells, without any visible signs of apoptosis.…”

Section: Uv-irradiation Induces Stabilization Of P53 In Hepatoma Cellsupporting

confidence: 64%

“…(ii) Cells of the p53 wildtype 55.1c line are at least sensitive towards UV-induced apoptosis when compared to 70.4 cells. 9 One would therefore expect a comparable decrease in P53 protein in UV-irradiated 55.1c cells, in particular since the half-life of the wild-type protein is much shorter than that of the mutant form. This effect, however, was clearly not observed.…”

Section: Discussionmentioning

confidence: 99%

“…Both UV-light and DFX induce apoptosis of mouse hepatoma cells, an effect which is independent of functional P53. 9 The decrease in P53 in UV-exposed 70.4 cells may therefore be linked to induction of apoptosis in the irradiated cells. Apoptotic cells may slow down RNA synthesis, which would lead to a disappearance of short-lived proteins in the cells.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Upon treatment of the p53 defective cells with UV-light, we observed a nearly complete disappearance of P53 protein 24 hr after irradiation (Figs. 1d, 1f and 1h).…”

Section: P53 Levels Are High In P53 Mutated Cell Lines and Decrease Amentioning

confidence: 99%

“…9 Western blot analysis of P53 (Fig. 4a) clearly indicated that the concentration of total P53 increases in 56.1b cells 6-24 hr after UV-irradiation, as seen in p53 wildtype cells.…”

Section: Uv-irradiation Induces Stabilization Of P53 In Hepatoma Cellmentioning

confidence: 99%

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Regulation of P53 stability in p53 mutated human and mouse hepatoma cells

Hailfinger

Jaworski

Marx‐Stoelting

et al. 2007

Intl Journal of Cancer

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The tumor suppressor p53 is frequently mutated in cancer. We have investigated the regulation of P53 in p53 wild type mouse hepatoma cells (line 55.1c), in p53 heterozygeously mutated cells (56.1b) and in p53 defective cells (lines 56.1d, 70.4 and HUH7) under various experimental settings. The basal levels of P53 were low in 55.1c cells, but nuclear accumulation occurred upon UVirradiation. Similarly, UV-exposure induced stabilization of P53 in the heterozygeously p53 mutated 56.1b hepatoma cells. By contrast, the 3 hepatoma lines, which lack transcriptionally active P53, demonstrated high basal nuclear concentrations of P53 protein and, unexpectedly, showed loss of P53 upon UV-irradiation. Expression of p53 mRNA was also decreased in p53 defective cells after 24 hr post UV-irradiation, which may be linked to induction of apoptosis of the irradiated cells under these conditions. Other stressors like H 2 O 2 also mediated a decrease in P53 concentration in p53 defective cells. This effect occurred at very low concentrations and was already detectable 1-2 hr after exposure of cells. There were no signs of apoptosis of H 2 O 2 -exposed cells at this time point and no significant changes in p53 mRNA or MDM2 level. These unexpected findings indicate a new aspect related to regulation of P53 stability in cells with a defect in the tumor suppressor protein. ' 2007 Wiley-Liss, Inc.Key words: p53 mutation; hepatoma cells; MDM2; DFX; UV irradiation; ROS The p53 tumor suppressor protein is a powerful cellular caretaker, which protects cells from malignant transformation by means of transcriptional upregulation of proapoptotic, DNA repair and cell cycle arrest related proteins. In unstressed cells the P53 level is kept low by the E3 ubiquitin ligase MDM2, which transfers activated ubiquitin residues to P53. 1 Polyubiquitination of P53 leads to a rapid proteasomal degradation of the tumor suppressor, preventing P53 from affecting the cells' viability. P53 itself transcriptionally upregulates MDM2 expression, forming a negative feedback loop.Stress signals, caused by UV-light, DNA-damaging agents or hypoxia lead to an activation of several kinases, of which the most prominent members are the ATM (ataxia-telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related), DNA-dependent protein kinase and casein kinase II, which phosphorylate the P53 protein at different sites (for review see Ref.2). Polyphosphorylation at the N-terminus of P53 reduces MDM2-dependent degradation, leading to an accumulation of the P53 protein in the cell followed by upregulation of apoptosis or cell cycle arrest related proteins. Exposure of cells to UV light correlates with post-translational modifications of P53, such as phosphorylation of serine 15 (mouse serine 18) and serine 20 (mouse serine 23). Desferrioxamine (DFX) treatment, which mimics hypoxia, results in phosphorylation of serine 15. Both sites are known to reduce MDM2-binding when phosphorylated. 3

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Section: Uv-irradiation Induces Stabilization Of P53 In Hepatoma Cellsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…9,10 Upon treatment of the p53 defective cells with UV-light, we observed a nearly complete disappearance of P53 protein 24 hr after irradiation (Figs. 1d, 1f and 1h).…”

Section: P53 Levels Are High In P53 Mutated Cell Lines and Decrease Amentioning

confidence: 99%

“…9 Western blot analysis of P53 (Fig. 4a) clearly indicated that the concentration of total P53 increases in 56.1b cells 6-24 hr after UV-irradiation, as seen in p53 wildtype cells.…”

Section: Uv-irradiation Induces Stabilization Of P53 In Hepatoma Cellmentioning

confidence: 99%

See 3 more Smart Citations

Regulation of P53 stability in p53 mutated human and mouse hepatoma cells

Hailfinger

Jaworski

Marx‐Stoelting

et al. 2007

Intl Journal of Cancer

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Distinct p53-independent apoptotic cell death signalling pathways in testicular germ cell tumour cell lines

Burger¹,

Nooter²,

Boersma³

et al. 1999

Int. J. Cancer

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Fas receptor‐mediated apoptosis: a clinical application?

Timmer

Vries

Jong

2001

The Journal of Pathology

116

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Fas is a membrane protein belonging to the death receptor family. Cross-linking of Fas by its ligand, FasL, or agonistic anti-Fas antibodies, induces apoptosis of cells expressing Fas on the membrane by triggering a cascade of caspases. Since many different tumours express Fas on their membrane, targeting Fas-mediated apoptosis by anti-Fas antibodies may be a promising anticancer therapy. Unfortunately, not all Fas-expressing cells are sensitive to Fas-mediated apoptosis. This has resulted in the discovery of many different inhibition mechanisms of Fas-mediated apoptosis. In addition, mutations in the Fas or p53 gene can also influence the sensitivity for Fas-mediated apoptosis. However, the role of wild-type p53 in Fas expression is still controversial. Because several different cytotoxic drugs are able to induce Fas membrane expression, combination therapy of anticancer drugs with anti-Fas antibodies or FasL is conceivable as an anticancer strategy. The efficiency of the induction of Fas-mediated apoptosis by anti-Fas antibodies, FasL-expressing cells or recombinant FasL (rFasL) in tumours has been demonstrated in vivo in solid tumours implanted in mice. Unfortunately, systemic treatment with anti-Fas antibodies or rFasL causes severe damage to the liver, so most preclinical studies are now focusing on circumvention of this problem by local administration of FasL, or on the use of inducible FasL-expressing vectors as gene therapy.

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Wild-type function of the p53 tumor suppressor protein is not required for apoptosis of mouse hepatoma cells

Cited by 21 publications

References 31 publications

Regulation of P53 stability in p53 mutated human and mouse hepatoma cells

Regulation of P53 stability in p53 mutated human and mouse hepatoma cells

Distinct p53-independent apoptotic cell death signalling pathways in testicular germ cell tumour cell lines

Fas receptor‐mediated apoptosis: a clinical application?

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