Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Preis 1999

Dr. Jean Schneikert

Institut für Genetik, Forschungszentrum Karlsruhe

Differential regulation of transactivation and transrepression functions of glucocorticoid receptor by RAP46/Bag-1M

Glucocorticoids are widely used pharmacologically as antiinflammatory agents although their long-term application is associated with adverse side effects. A lot of effort is therefore being made to understand the molecular basis of their action that would allow the discrimination between their wanted from their unwanted effects.

At the molecular level, glucocorticoids diffuse passively through the membrane of the cell and bind to a specific cytoplasmic receptor, the glucocorticoid receptor (GR). This liganded receptor then translocates into the nucleus where it modulates the expression of target genes, either positively or negatively. Some of the genes that are negatively regulated by the GR encode mediators of inflammation and other positively regulated genes may take part in the adverse effects of glucocorticoids. Therefore, one goal of our research is to separate the positive from the negative controls of the GR on gene expression, with a view of dissociating the pharmacological activities of this receptor.

One of the ways whereby such dissociation of activities of the GR can be achieved is through the modulation of the level of factors that bind to the receptor to control its activity. Such a factor may be RAP46 also known as either HAP46 or Bag1M. RAP46 is a protein isolated by virtue of its ability to physically associate with the GR. In functional assays, it modulates the transcriptional regulatory property of the GR. Although RAP46 is located in the cytoplasm, it does not significantly affect the binding of hormone to the receptor. It is rather recruited into the nucleus by the receptor once it has bound the hormone. In the nucleus, RAP46 inhibits binding of the receptor to DNA, leading to a reduction of the level of gene expression induced by the GR. In contrast, it does not alter the property of the GR to repress gene expression. Thus, RAP46 distinguishes between the transactivation and the transrepression functions of the GR. This protein is therefore a likely candidate for dissociation of the pharmacological actions of the GR.



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