Endocrine Abstracts

Nur77 is a nuclear orphan receptor belonging to the steroid receptor superfamily. A role for Nur77 has been described in proliferation, differentiation and apoptosis, as a result of its induction in response to multiple signal transduction pathways. Previous studies have suggested that physical interaction between Nur77 and the tumor suppressor p53 can prevent p53 ubiquination and subsequent degradation by hMdm2. This suggests a possible role for Nur77 as a regulator of p53-dependent signals.

To further investigate the interaction between these two proteins, we first studied if p53-dependent apoptotic responses are modified by the absence of Nur77. Wildtype and Nur77 mouse embryo fibroblast were sensitized by infection with the oncoviral protein E1A and subsequent treated with Doxorubicin or Cisplatin. We observed that apoptosis was partially reduced in absence of Nur77, even though p53 was equally estabilized in these cells when compared to the Wildtype. Thus, these results indicate that Nur77 is a mediator of p53-dependent apoptotic responses.

A possible regulation of Nur77 by p53 was also explored by analyzing Nur77 mRNA levels after treatment with genotoxic agents. HCT116 colorectal carcinoma cells cultured in presence of Doxorubicin or Cisplatin showed a higher increase on Nur77 mRNA when compared with their counterpart p53−/−. Sequence analysis showed the presence of a canonical p53-binging site whitin Nur77 gene. By cloning this site on a luciferase reporter system we were able to detect an increase on the reporter activity in the presence of both endogenous or transfected p53. Site-directed mutagenesis on this sequence led to a marked reduction on the reporter signal confirming the specificity of the regulation.

Taken together our results indicate that Nur77 is a p53-responsive gene that is mediating, at least in part, p53-dependent apoptotic responses.

This study was funded by Fundación de Investigacion Medica Mutua Madrileña and Xunta de Galicia.