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Institut für Molekularbiologie und Tumorforschung, Philipps Universität, D-35037 Marburg, Germany
A short conserved 
-helix in the
carboxyl-terminal activation function of the ligand-binding domain of
steroid hormone receptors, called AF2, is important for
ligand-dependent transactivation of inducible genes. We have generated
two AF2 mutants of the B isoform of human progesterone receptor (PRB):
a point mutant, PRBE911A, and a short deletion, PRB
907–913R. The
two mutants are expressed at levels comparable to the wild type
receptor in transfected cells. The PRBE911A mutant showed similar
hormone- and DNA- binding affinities as the wild type receptor, whereas
the PRB907–913R mutant was defective in hormone and DNA binding.
Both mutants were inactive when transiently transfected in CV-1 cells,
which do not express endogenous PR. However, the point mutant, but not
the deletion mutant, inhibited transactivation by cotransfected wild
type PRB in a hormone-dependent fashion. The activity of endogenous PR
in T47D cells or of endogenous glucocorticoid receptor in HeLa cells
was also inhibited by the PRBE911A, but not by the deletion mutant. The
point mutant was less active when introduced into an N-terminal
truncated form of PR, where it gave rise to proteins that formed
homodimers with poor affinity for DNA, but were able to form
heterodimers with PRB. The negative dominant phenotype of the PRBE911A
mutant likely originates from competition with wild type receptors for
binding to DNA and will be useful for mechanistic studies of receptor
function.
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