The FK506-binding immunophilin FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness.

Hubler TR, Denny WB, Valentine DL, Cheung-Flynn J, Smith DF, Scammell JG
Endocrinology. 2003 144 (6): 2380-7

PMID: 12746298 · DOI:10.1210/en.2003-0092

FKBP51 and FKBP52 are large molecular weight FK506-binding immunophilins that have diverse biochemical functions. Best studied is the role that they play as components of steroid hormone receptors. Differential display and gene array screens have identified FKBP51 as a progestin-inducible gene. Here we demonstrate progestin enhancement of FKBP51 mRNA and protein in T-47D cells. FKBP51 mRNA and protein levels were increased 3-fold by 20 nM R5020. Induction of FKBP51 mRNA was unaffected by 1 micro g/ml cycloheximide but was blocked by the progestin receptor (PR) antagonist RU486 (1 micro M). Reporter plasmids containing 3.4 kb and 427 bp of 5'-flanking sequences of the human FKBP51 protein gene (FKBP5) exhibited regulation by progestin in T-47D cells. A construct containing 19 bp of upstream sequence demonstrated diminished basal activity and no stimulation by R5020. To test whether elevated FKBP51 affects progestin responsiveness, HepG2 cells were transfected with human FKBP51, PR, and mouse mammary tumor virus-luciferase plasmids, and treated with R5020 (0.03-10 nM). Expression of FKBP51 increased the EC(50) for PR transactivation by 3.2-fold. Expression of FKBP51 from squirrel monkey, a New World primate with naturally occurring progestin resistance, increased the EC(50) more dramatically (11.7-fold vs. control). Expression of FKBP51 bearing a double-point mutation in the tetratricopeptide repeat domain had no effect on PR transactivation. These results suggest that increased expression of FKBP51 by progestin may attenuate progestin responsiveness in hormone-conditioned cells. Furthermore, overexpression of FKBP51 in the squirrel monkey may be a contributing cause of progesterone resistance in this species.

MeSH Terms (17)

Animals Base Sequence Breast Neoplasms Carcinoma, Hepatocellular Gene Expression Humans Liver Neoplasms Molecular Sequence Data Progesterone Congeners Promegestone Promoter Regions, Genetic Saimiri Sequence Homology, Nucleic Acid Tacrolimus Tacrolimus Binding Proteins Transcription, Genetic Tumor Cells, Cultured

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