Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells
Sagar Sengupta,
Jean-Luc Vonesch,
Caroline Waltzinger,
Hong Zheng, and
Bohdan Wasylyk1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, 67404 Illkirch cedex, France 1Corresponding author e-mail: boh{at}igbmc.u-strasbg.fr
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 p21WAF1/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.
Key Words: Keywords: apoptosis/cell cycle/cellular localization/GR antagonists/neuroblastoma
