ΔTAp73 Upregulation Correlates With Poor Prognosis in Human Tumors: Putative In Vivo Network Involving p73 Isoforms, p53, and E2F-1

Domínguez, Gemma; García, José M.; Peña, Cristina; Silva, Javier; Garcı́a, Vanesa; Martínez, L Crespo; Maximiano, Constanza; Gomez, Maria; Hernández-Rivera, Juan Carlos H; García-Andrade, Carmen; Bonilla, Félix

doi:10.1200/jco.2005.02.2350

Cited by 113 publications

(131 citation statements)

References 34 publications

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“…DNp73 isoforms (also called DTAp73) include the DNp73 AS isoforms generated by alternative splicing (AS) at the NH 2 -terminus and the DNp73 AP isoform transcribed from an AP located in intron 3 (Figure 1). The overexpression of DNp73 isoforms occurs in a variety of cancers and has also been identified as a poor prognostic marker in patients with ovarian (Concin et al, 2005), hepatocellular (Muller et al, 2005), colon and breast cancers (Dominguez et al, 2006), and in children with neuroblastoma (Casciano et al, 2002). p73 splice variants are also generated at the COOH-terminus (a-y), and these proteins possess some differences in their intrinsic ability to induce target genes and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

et al. 2009

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p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms contain a transactivation (TA) domain, and like p53, have tumor suppressor properties and are activated by chemotherapies to induce cell death. In contrast, antiapoptotic DNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. DNp73 proteins are overexpressed in a variety of tumors including neuroblastoma. Thus, identification of drugs that upregulate TAp73 and/or downregulate DNp73 represents a potential therapeutic strategy. Here, we report that cyclooxygenase (COX) inhibitors induce apoptosis independent of p53, and differentially modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX inhibitor-mediated apoptosis is associated with the induction of TAp73b and its target genes. COX inhibitors also downregulate the alternative-spliced DNp73 AS isoforms, Dexon2 and Dexon2/3. Furthermore, forced expression of DNp73AS results in diminished apoptosis in response to the selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of DNp73AS is associated with decreased E2F1 levels and diminished E2F1 activation of the p73 promoter. These results provide the first evidence that COX inhibitors differentially modulate p73 isoforms leading to enhanced apoptosis, and support the potential use of COX inhibitors as novel regulators of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those with wild-type (wt) or mutant p53.

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Section: Introductionmentioning

confidence: 99%

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

et al. 2009

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“…In mice, DNp73 features proto-oncogenic properties; it facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation and in tumorigenesis (Stiewe and Putzer, 2002;Petrenko et al, 2003). Expression of DNp73 correlates with poor patient prognosis in neuroblastoma, lung, ovarian, prostate, colon and breast cancers (Casciano et al, 2002;Guan and Chen, 2005;Dominguez et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

ΔNp73α regulates MDR1 expression by inhibiting p53 function

et al. 2007

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The p73 protein is a transcription factor and member of the p53 protein family that expresses as a complex variety of isoforms. DNp73a is an N-terminally truncated isoform of p73. We found that DNp73 protein is upregulated in human gastric carcinoma suggesting that DNp73 may play an oncogenic role in these tumors. Although it has been shown that DNp73a inhibits apoptosis and counteracts the effect of chemotherapeutic drugs, the underlying mechanism by which this p73 isoform contributes to chemotherapeutic drug response remains to be explored. We found that DNp73a upregulates MDR1 mRNA and pglycoprotein (p-gp), which is involved in chemotherapeutic drug transport. This p-gp upregulation was accompanied by increased p-gp functional activity in gastric cancer cells. Our data suggest that upregulation of MDR1 by DNp73a is mediated by interaction with p53 at the MDR1 promoter.

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“…On the contrary, up-regulation of p73 was frequently observed. In particular, deregulated expression of isoforms containing a truncated TA domain, especially ⌬Np73, has been demonstrated in several human cancers (27,28). p73 isoforms lacking the TA domain are transactivation-deficient and do not induce growth suppression or cell death.…”

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confidence: 99%

TAp73 Induction by Nitric Oxide

Tebbi

Guittet

Cottet

et al. 2011

Journal of Biological Chemistry

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Nitric oxide (NO) is a potent activator of the p53 tumor suppressor protein, thereby inducing cell cycle arrest and apoptosis. However, little is known about the regulation of the two other p53-family members, p63 and p73, by nitrogen oxides. We report here an up-regulation of p73 by NO in p53-null K-562 leukemia cells. Chemical NO prodrugs or macrophage iNOS activity induced an accumulation of the TAp73␣ isoform in these cells, whereas macrophages from iNOS ؊/؊ mice did not. NO is a free radical implicated in numerous physiological functions. In cancer biology, both positive and negative actions of NO have been reported. For example, NO was found to promote tumor growth angiogenesis, and metastasis on the one hand and to induce apoptotic cell death or tumor cytostasis on the other hand (1-4). These opposite responses are linked to the chemistry of nitric oxide in a cellular context. NO not only reacts directly on target molecules but also exerts its effects through derived species with a higher degree of oxidation and generated from NO interaction with O 2 (e.g. N 2 O 3 , ⅐ NO 2 ) or superoxide anion (ONOO Ϫ ). Those reactive nitrogen species can act as potent nitrosating, nitrating, or oxidizing agents. Given this complex chemistry, the biological outcome of NO is directed by its concentration, the cellular redox environment, and different target susceptibilities. High fluxes of NO are generated by inducible NO synthase (iNOS), 3 transcriptionally induced in immune cells such as macrophages by cytokines and bacterial products (e.g. IFN-␥ and lipopolysaccharide). Elevated concentrations of NO cause DNA damage, mutation, and apoptotic cell death (5, 6). The tumor suppressor protein p53 is a key player in the DNA damage response and the onset of apoptosis. NO has been shown to activate p53 at high concentrations, which also promote genotoxic and pro-apoptotic effects (3, 6, 7). Because p53 is a transcription factor regulating the expression of several genes involved in DNA repair, cell cycle arrest, and apoptosis, activation of p53 by NO can be considered as a regulatory mechanism preventing the emergence of NO-induced DNA mutations and, hence, tumorigenesis. Augmentation of mutation rates in p53-deficient cells exposed to high NO doses and repression of iNOS gene transcription by p53 in a negative feedback loop are occurrences that strongly support a major role for p53 in the control of NO-induced genotoxicity (7-9). NO also up-regulatedTwo p53-related genes, p63 and p73, have been identified more than 15 years after the discovery of p53 (10, 11). The p53 family members have a similar structural organization comprising an NH 2 -terminal transactivation domain (TA), a central DNA binding domain, and a COOH-terminal oligomerization domain (12-15). In p63 and p73, an additional sterile-␣ motif and a transcription inhibitory domain may follow the oligomerization domain. Sequence homology among the three members is limited to 25-40% identity between TA and oligomerization domain regions but increases to 60 -80% amino...

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ΔTAp73 Upregulation Correlates With Poor Prognosis in Human Tumors: Putative In Vivo Network Involving p73 Isoforms, p53, and E2F-1

Cited by 113 publications

References 34 publications

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

ΔNp73α regulates MDR1 expression by inhibiting p53 function

TAp73 Induction by Nitric Oxide

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