Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line

Goldschneider, David; Blanc, Étienne; Raguénez, Gilda; Barrois, Michel; Legrand, Agnès; Roux, G. Le; Haddada, Hédi; Bénard, Jean; Douc‐Rasy, Sétha

doi:10.1242/jcs.00834

Cited by 32 publications

(40 citation statements)

References 35 publications

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“…In the absence of cisplatin, p53 protein accumulation was induced by TAp73· as well as by ΔNp73· overexpression, as has been previously reported using the adenoviral system (14). This accumulation in untreated SH-SY5Y cells might be the result of stabilization induced by competition for MDM2 as p73 is known to form a stable complex with MDM2 (18,19).…”

Section: Tap73· and δNp73· Differentially Regulate P53/p73 Target Gensupporting

confidence: 77%

“…Importantly, ΔNp73 is known to play a role in various human tumors (11) whereas TAp73 may be involved in development and differentiation processes in normal cells, particularly in neurons (12). In previous studies, we reported that ΔNp73 is the only accumulated isoform in undifferentiated NB (13), and that TAp73· cooperates with wt-p53 to efficiently induce apoptosis (14).…”

Section: Introductionmentioning

confidence: 92%

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Differential regulation of p73 variants in response to cisplatin treatment in SH-SY5Y neuroblastoma cells

Million

Emilie²,

Goldschneider³

et al. 2006

Int J Oncol

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Abstract. The present study aims to investigate the role of p73 in response to cisplatin treatment in p53 wild-type neuroblastoma SH-SY5Y cells. Results showed that cisplatin induced a dose-dependent up-regulation of p53, p73, and a number of p53-responsive genes. Interestingly, endogenous Δexon2p73-expression was down-regulated by cisplatin treatment. Neither p21 nor GADD45 induction was observed in p53-deficient Lan-1 cells, although endogenous TAp73 expression was markedly induced. In the presence of cisplatin, exogenous TAp73 overexpression in SH-SY5Y cells induced p21 upregulation without altering the apoptotic sub-G1 cell population. Moreover, siRNA-mediated suppression of TAp73 expression did not alter the sub-G1 population. Collectively, our results suggest that wt-p53 SH-SY5Y cells respond to cisplatin by inducing p73 isoform regulation and sustaining p53-dependent apoptosis that is independent of TAp73·. IntroductionNeuroblastoma (NB) is a malignant solid tumor of early childhood which is derived from neural crest precursor cells. Of the antitumor agents used in NB induction chemotherapy, cisplatin is known to exert cytotoxic effects as a result of DNA lesions involving the formation of intra-strand adducts. The resulting inhibition of DNA synthesis is associated with transcription arrest and subsequent cell-cycle inhibitory effects and apoptosis. Unlike most human tumors, NB cells do not exhibit mutated p53 at diagnosis. NB tumors from heavily treated patients can acquire high-level drug resistance during cytotoxic therapy. The subsequent loss of p53 function (1,2) is thought to be possibly due to a series of mutations (3). The p73 protein, which is a structural and functional homologue of the p53 protein, is capable of activating specific target genes and inducing cell-cycle arrest and apoptosis (4,5). Moreover, TPp73 encodes several different isoforms generated by the use of a second promoter or alternative 3'-end splicing (6). The N-terminus of the protein exists in various shorter isoforms that lack a transactivation (TA) domain. The dominant negative inhibitor, ΔNp73·, and the full-length TAp73· are the most studied isoforms to date. Despite the fact that it is located on chromosome 1p36.3, a chromosome which undergoes frequent loss of heterozygosity in some cancers such as NB, the TPp73 gene is rarely mutated in human tumors (7). Recently, it was reported that the TAp73 protein can induce apoptosis through different mechanisms. For that matter, TAp73 in Saos-2 osteosarcoma cells lacking p53 elicits endoplasmic reticulum stress due to the overexpression of scotin, an apoptosis mediator (8). Besides, p73 could activate the death receptors through PUMA transactivation and via Bax mitochondrial translocation (9). Other investigators found that, in the U373MG astroma cell line lacking endogenous p53 (p53 -/p73 + ), TAp73 can sentisize cells to apoptosis through Fas signaling pathway and showed that this apoptosis depends on caspase activation but is not due to variations in deathinducing signaling co...

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Section: Tap73· and δNp73· Differentially Regulate P53/p73 Target Gensupporting

confidence: 77%

Section: Introductionmentioning

confidence: 92%

Differential regulation of p73 variants in response to cisplatin treatment in SH-SY5Y neuroblastoma cells

Million

Emilie²,

Goldschneider³

et al. 2006

Int J Oncol

Self Cite

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“…In this study, we investigated the ability of nutlin-3 to induce apoptosis in a p53-null and doxorubicin-resistant NB cell line, LA155N. LA155N contains p73, a homologue of p53 which occurs in multiple isoforms and is required for some NB cell differentiation (9,10,12). It is known that the p73 gene has at least two promoters and the resulting protein products have distinct and opposing effects.…”

Section: Introductionmentioning

confidence: 99%

The MDM2 antagonist nutlin-3 sensitizes p53-null neuroblastoma cells to doxorubicin via E2F1 and TAp73

Peirce¹

2009

Int J Oncol

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Abstract. Neuroblastoma (NB) is a primitive neuroectodermal tumor and the second most common solid tumor in children. NB exhibits heterogeneous behavior and spontaneous regression can occur in patients under 12 months of age. Response to treatment is both age-and stage-specific; however, patients over 1 year of age are generally considered high risk. NB tumors from these patients are often characterized by alterations in p53 expression and murine double minute (MDM2) activity with concomitant resistance to chemotherapy. We evaluated the ability of nutlin-3 to sensitize a p53-null and doxorubicin-resistant NB cell line, LA155N, to doxorubicin. Nutlin-3 treatment upregulated TAp73 and E2F1 protein levels. It potentiated the ability of doxorubicin to block cell proliferation and activate apoptosis and TAp73 knockdown resulted in a reduction of this sensitization. Additionally, PUMA expression was induced by the combination treatment, but reduced by knockdown of either TAp73 or E2F1. We conclude that, following nutlin-3 treatment, TAp73 and E2F1 are released from MDM2 and activated by doxorubicin to induce PUMA and apoptosis. This study addresses p53-independent mechanisms of nutlin-3 action in chemoresistant NB, especially in combination with chemotherapeutics. We believe that this model has strong clinical relevance for chemoresistant and p53 dysfunctional NB.

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“…Like UR61 cells, the human SH-SY5Y and NTera2 cells contain a wild-type p53 gene [22][23][24] To determine whether p73 activation of the MAPK cascade was independent of p53 status, we performed a similar experiment in SaOs-2, a p53 null human osteosarcoma cell line with no oncogenic Ras, 25 and in HCT116p53À/À cells. Ectopic expression of TAp73a and b induced Elk1 activity (Figure 5a and b) in both cell lines.…”

Section: Resultsmentioning

confidence: 99%

p73 cooperates with Ras in the activation of MAP kinase signaling cascade

et al. 2006

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The p73 gene is capable of inducing cell cycle arrest, apoptosis, senescence, differentiation and to cooperate with oncogenic Ras in cellular transformation. Ras can be considered as a branch point in signal transduction, where diverse extracellular stimuli converge. The intensity of the mitogen-activated protein kinase (MAPK) cascade activation influences the cellular response to Ras. Despite the fundamental role of p53 in Ras-induced growth arrest and senescence, it remains unclear how the Ras/MEK/ERK pathway induces growth arrest in the absence of p53. We report here that oncogenic Ras stabilizes p73 resulting in p73 accumulation and enhancement of its activity. p73, in turn, induces a sustained activation of the MAP kinase cascade synergizing with oncogenic Ras. We also found that inhibition of p73 function modifies the cellular outcome to Ras activation inhibiting Ras-dependent differentiation. Here, we show for the first time that there is a signaling loop between Ras-dependent MAPK cascade activation and p73 function.

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Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line

Cited by 32 publications

References 35 publications

Differential regulation of p73 variants in response to cisplatin treatment in SH-SY5Y neuroblastoma cells

Differential regulation of p73 variants in response to cisplatin treatment in SH-SY5Y neuroblastoma cells

The MDM2 antagonist nutlin-3 sensitizes p53-null neuroblastoma cells to doxorubicin via E2F1 and TAp73

p73 cooperates with Ras in the activation of MAP kinase signaling cascade

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