Regulation Of Corticosteroid-binding Globulin Gene Expression

Corticosteroid-binding globulin (CBG) is a plasma glycoprotein that transports glucocorticoids and progesterone. Strain specific variations were found in rodent CBG coding sequences. Amino acid substitutions at positions 276 and 285 classify CBG of 8 rat inbred strains into 3 groups, and a {dollar}\rm Val\sp{lcub}285{rcub}\to Met{dollar} substitution seems to compensate the detrimental effect of the {dollar}\rm Met\sp{lcub}276{rcub}\to Ile{dollar} substitution on rat CBG steroid-binding affinity. Characterization of a mouse RIIIS/J CBG cDNA identified a single amino acid substitution (Lys{dollar}\sp{lcub}201{rcub}\to{dollar} Glu) that is responsible for the reduced steroid-binding affinity in RIIIS/J CBG. Exogenous glucocorticoids were shown to promote an increase of mouse CBG gene expression in both liver and kidney during postnatal development. The CBG gene in the liver and kidney responds similarly to glucocorticoids prior to 3 weeks of age but its glucocorticoid-dependence in these tissues differs after this age. Characterization of rat liver nuclear proteins that bind to the 5 potential cis-elements (P1-P5) in rat CBG promoter indentified HNF1{dollar}\alpha{dollar} and HNF1{dollar}\beta{dollar} as proteins that bind the P1 element; a CCAAT-binding protein with a molecular weight of {dollar}\sim{dollar}65 kDa binds P2; a nuclear protein of {dollar}\sim{dollar}50 kDa was found to bind P3 element but its identity is still not clear; the major protein that binds P4 is most likely HNF3 considering its binding site DNA sequences and molecular weight; nuclear proteins of {dollar}\sim{dollar}20, 30 and 40 kDa were UV crosslinked to P5 and probably belong to the C/EBP family of nuclear proteins. Competition between P1 and P2, P1 and P4 for binding nuclear proteins was observed and may contribute to the regulation of CBG gene expression. The activation of rat CBG gene expression during postnatal development requires the cooperation of several nuclear proteins that interact with the cis-elements in proximity to the transcription initiation site, and I have obtained evidence that the {dollar}\sim{dollar}65 kDa P2-binding protein may play a key role in this regard