Article
- The EMBO Journal (2000) 19, 6051 - 6064
- doi:10.1093/emboj/19.22.6051
Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells
Sagar Sengupta1, Jean-Luc Vonesch1, Caroline Waltzinger1, Hong Zheng1 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
Correspondence to:
Bohdan Wasylyk, E-mail: boh@igbmc.u-strasbg.fr
Received 27 June 2000; Accepted 10 August 2000; Revised 8 August 2000
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.
Keywords:
- apoptosis,
- cell cycle,
- cellular localization,
- GR antagonists,
- neuroblastoma
