Direct transactivation of c-Ha-Ras gene by p53: evidence for its involvement in p53 transactivation activity and p53-mediated apoptosis

Deguin-Chambon, Valérie; Vacher, Monique; Jullien, Martial; May, Evelyne; Bourdon, Jean-Christophe

doi:10.1038/sj.onc.1203960

Cited by 25 publications

(22 citation statements)

References 55 publications

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“…Two independent clones were analyzed in parallel. As already reported, 28 the p53DD expression stabilizes MCF-7-endogenous wt-p53 ( Figure 2A, lanes`+tet'), but inhibits its transcriptional activity as shown by transient expression of luciferase reporter gene under the control of a p53 responsive element ( Figure 2B). However, the p53DD expression ( Figure 2C, lanes`+tet') had no effect on the increase of p21/Waf1 mRNA level brought by TNFa treatment.…”

Section: Resultsmentioning

confidence: 49%

Accumulation of an inactive form of p53 protein in cells treated with TNFα

et al. 2002

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In MCF-7 cells, TNFa induces a G1 arrest with an increased expression of p21/Waf1, an activation of NF-kB and an accumulation of p53. NF-kB and p53 are two transcriptional factors known to activate p21/Waf1 gene expression. Here we show that p53 inhibition has no effect on p21/Waf1 mRNA accumulation following TNFa treatment. In contrast, inactivation of NF-kB inhibits p21/Waf1 expression without affecting G1 arrest. The fact that p21/Waf1 gene expression is still stimulatedwhenp53isinactivatedstronglysuggeststhatTNFa induces accumulation of an inactive form of p53 protein. This assumption was further supported by the following observations: (i) the p53 DNA-binding activity to its consensus sequence was not stimulated following TNFa treatment, (ii) phosphorylation at Ser-15, -20 or -392 was not detected in response to TNFa, (iii) the transcription rate of Ddb2, another p53 target gene, was not stimulated by TNFa. Finally, the accumulation of p53 in the nuclei of TNFa-treated MCF-7 cells was concomitant with an increase in p53 mRNA level, suggesting a regulation at the transcription level.

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Section: Resultsmentioning

confidence: 49%

Accumulation of an inactive form of p53 protein in cells treated with TNFα

et al. 2002

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“…[4][5][6] Furthermore, it was also observed that the activation of the Ras/MAPK pathway is involved in the p53-dependent apoptosis in response to DNA damage. 9,35 Here we show that p53 can directly counteract the Ras/MAPK pathway by promoting a caspase-mediated ERK2 cleavage. In particular, upon DNA damage, we have found an early increase of the ERK2 expression and phosphorylation followed by a strong downregulation.…”

Section: P53 Counteracts the Ras/mapk Cascadementioning

confidence: 71%

“…7 Recently, induction of apoptosis by DNA damage or p53 overexpression was shown to correlate with increased levels of phosphorylated ERK2 and p53-mediated transcriptional activation of the ras promoter. 8,9 Interestingly, the opposite effect (i.e., resistance to apoptosis) was also found to depend on the inhibition of p53 function by Ras/ MAPK pathway through the transcriptional activation of the Mdm2 gene. 5 The ability of Ras to activate p53 has been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

Marchetti

Cecchinelli²,

D'Angelo³

et al. 2004

Cell Death Differ

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Stimulation of the Ras/MAPK cascade can either activate p53 and promote replicative senescence and apoptosis, or degrade p53 and promote cell survival. Here we show that p53 can directly counteract the Ras/MAPK signaling by inactivating ERK2/MAPK. This inactivation is due to a caspase cleavage of the ERK2 protein and contributes to p53-mediated growth arrest. We found that in Ras-transformed cells, growth arrest induced by p53, but not p21 Waf1 , is associated with a strong reduction in ERK2 activity, phosphorylation, and protein half-life, and with the appearance of caspase activity. Likewise, DNA damage-induced cell cycle arrest correlates with p53-dependent ERK2 downregulation and caspase activation. Furthermore, caspase inhibitors or expression of a caspase-resistant ERK2 mutant interfere with ERK2 cleavage and restore proliferation in the presence of p53 activation, indicating that caspase-mediated ERK2 degradation contributes to p53-induced growth arrest. These findings strongly point to ERK2 as a novel p53 target in growth suppression.

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“…DNA was stained by propidium iodide. Cells were analyzed by flow cytometry (FACScan; Becton Dickinson) using a three-parameter analysis (Deguin-Chambon et al 2000).…”

Section: Facscan Analysismentioning

confidence: 99%

p53 isoforms can regulate p53 transcriptional activity

Bourdon¹,

Fernandes²,

et al. 2005

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The recently discovered p53-related genes, p73 and p63, express multiple splice variants and N-terminally truncated forms initiated from an alternative promoter in intron 3. To date, no alternative promoter and multiple splice variants have been described for the p53 gene. In this study, we show that p53 has a gene structure similar to the p73 and p63 genes. The human p53 gene contains an alternative promoter and transcribes multiple splice variants. We show that p53 variants are expressed in normal human tissue in a tissue-dependent manner. We determine that the alternative promoter is conserved through evolution from Drosophila to man, suggesting that the p53 family gene structure plays an essential role in the multiple activities of the p53 family members. Consistent with this hypothesis, p53 variants are differentially expressed in human breast tumors compared with normal breast tissue. We establish that p53␤ can bind differentially to promoters and can enhance p53 target gene expression in a promoter-dependent manner, while ⌬133p53 is dominant-negative toward full-length p53, inhibiting p53-mediated apoptosis. The differential expression of the p53 isoforms in human tumors may explain the difficulties in linking p53 status to the biological properties and drug sensitivity of human cancer.[Keywords: Splice; promoter; Drosophila; cancer; p73; p63] Supplemental material is available at http://www.genesdev.org.

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Direct transactivation of c-Ha-Ras gene by p53: evidence for its involvement in p53 transactivation activity and p53-mediated apoptosis

Cited by 25 publications

References 55 publications

Accumulation of an inactive form of p53 protein in cells treated with TNFα

Accumulation of an inactive form of p53 protein in cells treated with TNFα

p53 can inhibit cell proliferation through caspase-mediated cleavage of ERK2/MAPK

p53 isoforms can regulate p53 transcriptional activity

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