title: Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells.
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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, 67404 Illkirch cedex, France.
authors.forename: S
authors.initials: S
authors.lastname: Sengupta
authors.forename: J L
authors.initials: JL
authors.lastname: Vonesch
authors.forename: C
authors.initials: C
authors.lastname: Waltzinger
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: B
authors.initials: B
authors.lastname: Wasylyk
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D046911:Macromolecular Substances; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D020239:Receptor Cross-Talk; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D046911:Macromolecular Substances; D011965:Receptors, Glucocorticoid; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone