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Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells
S Sengupta1, J L Vonesch, C Waltzinger
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, 67404 Illkirch cedex, France.
Abstract:
The tumour suppressor p53 and the glucocorticoid receptor (GR) respond to different types of stress. We found that dexamethasone-activated endogenous and exogenous GR inhibit p53-dependent functions, including transactivation, up- (Bax and p21(WAF1/CIP1)) and down- (Bcl2) regulation of endogenous genes, cell cycle arrest and apoptosis. GR forms a complex with p53 in vivo, resulting in cytoplasmic sequestration of both p53 and GR. In neuroblastoma (NB) cells, cytoplasmic retention and inactivation of wild-type p53 involves GR. p53 and GR form a complex that is dissociated by GR antagonists, resulting in accumulation of p53 in the nucleus, activation of p53-responsive genes, growth arrest and apoptosis. These results suggest that molecules that efficiently disrupt GR-p53 interactions would have a therapeutic potential for the treatment of neuroblastoma and perhaps other diseases in which p53 is sequestered by GR.
Insights
Glucocorticoid receptor (GR) inactivates the tumor suppressor p53 by forming a complex, leading to cytoplasmic sequestration. Disrupting this GR-p53 interaction could treat neuroblastoma and other diseases.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The tumor suppressor p53 and glucocorticoid receptor (GR) are key stress response proteins.
- p53 induces cell cycle arrest and apoptosis, while GR regulates gene expression in response to glucocorticoids.
Purpose of the Study:
- To investigate the interaction between p53 and GR and its functional consequences.
- To explore the therapeutic potential of targeting the GR-p53 complex in neuroblastoma.
Main Methods:
- In vivo complex formation studies.
- Analysis of gene regulation (Bax, p21, Bcl2).
- Cell cycle and apoptosis assays.
- Use of GR antagonists.
Main Results:
- Dexamethasone-activated GR inhibits p53-dependent functions, including gene regulation, cell cycle arrest, and apoptosis.
- GR forms a complex with p53, causing cytoplasmic sequestration and inactivation of p53.
- GR antagonists dissociate the p53-GR complex, leading to nuclear p53 accumulation, gene activation, growth arrest, and apoptosis in neuroblastoma cells.
Conclusions:
- GR actively inhibits wild-type p53 function in neuroblastoma cells through cytoplasmic sequestration.
- Disrupting the GR-p53 interaction represents a potential therapeutic strategy for neuroblastoma.