Relative binding affinities of testosterone, 19-nortestosterone and their 5α-reduced derivatives to the androgen receptor and to other androgen-binding proteins: a suggested role of 5α-reductive steroid metabolism in the dissociation of “myotropic” and “androgenic” activities of 19-nortestosterone

Androgens stimulate the expression of tight junction (TJ) proteins and the formation of the blood–testis barrier (BTB). Interactions of testosterone with the zinc transporter ZIP9 stimulate the expression of TJ-forming proteins and promote TJ formation in Sertoli cells. In order to investigate androgenic effects mediated by ZIP9 but not by the nuclear androgen receptor (AR), the effects of three tetrapeptides fitting the androgen binding site of ZIP9 were compared with those induced by testosterone in a Sertoli cell line expressing ZIP9 but not the AR. Three tetrapeptides and testosterone displaced testosterone-BSA-FITC from the surface of 93RS2 cells and stimulated the non-classical testosterone signaling pathway that includes the activation of Erk1/2 kinases and transcription factors CREB and ATF-1. The expression of the TJ-associated proteins ZO-1 and claudin-5 was triggered as was the re-distribution of claudin-1 from the cytosol to the membrane and nucleus. Furthermore, TJ formation was stimulated, indicated by increased transepithelial electrical resistance. Silencing ZIP9 expression by siRNA prevented all of these responses. These results are consistent with an alternative pathway for testosterone action at the BTB that does not involve the nuclear AR and highlight the significant role of ZIP9 as a cell-surface androgen receptor that stimulates TJ formation.

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Androgen-binding proteins in rat epididymis: properties of a cytoplasmic receptor for androgen similar to the androgen receptor in ventral prostate and different from androgen-binding protein (ABP)

Molecular and Cellular Endocrinology ◽

10.1016/0303-7207(75)90056-8 ◽

1975 ◽

Vol 3 (2) ◽

pp. 83-101 ◽

Cited By ~ 34

Author(s):

Donald J. Tindall ◽

Vidar Hansson ◽

William S. McLean ◽

E.Martin Ritzen ◽

Shihadeh N. Nayfeh ◽

...

Keyword(s):

Androgen Receptor ◽

Binding Proteins ◽

Binding Protein ◽

Ventral Prostate ◽

Androgen Binding Protein ◽

Rat Epididymis ◽

Androgen Binding

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A Novel Mutation in the Human Androgen Receptor Suggests a Regulatory Role for the Hinge Region in Amino-Terminal and Carboxy-Terminal Interactions

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0737 ◽

2008 ◽

Vol 93 (10) ◽

pp. 3691-3696 ◽

Cited By ~ 18

Author(s):

A. Deeb ◽

J. Jääskeläinen ◽

M. Dattani ◽

H. C. Whitaker ◽

C. Costigan ◽

...

Keyword(s):

Androgen Receptor ◽

Nuclear Localization ◽

Novel Mutation ◽

Poor Response ◽

Fold Increase ◽

Hinge Region ◽

Regulatory Role ◽

Amino Terminal ◽

Androgen Binding

Context: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the AIS. A crucial step in AR action is the interaction of the N and C termini. Objective: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C-termini interaction. Patient and Method: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization study was performed. Results: Androgen binding was normal, and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared with wild type (WT). A 3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; no response occurred when the mutated region of the AR was included (P < 0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR. Conclusions: A mutation in the hinge region impaired N/C-domain interaction in the presence of normal AR binding and nuclear localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.

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A 63-kDa protein with androgen-binding activity is not from the androgen receptor

Biochemistry and Cell Biology ◽

10.1139/o91-104 ◽

1991 ◽

Vol 69 (10-11) ◽

pp. 695-701 ◽

Cited By ~ 10

Author(s):

Klaus Wrogemann ◽

Gary Podolsky ◽

Jin Gu ◽

Eduardo Rosenmann

Keyword(s):

Androgen Receptor ◽

Binding Activity ◽

Water Soluble ◽

Two Dimensional ◽

Testicular Feminization ◽

Steroid Binding ◽

Androgen Binding ◽

New Protein ◽

Steroid Binding Protein

We have found a new protein in the heart of rat and mice that can be selectively and covalently labelled with the synthetic androgen analog mibolerone. Binding is specific as it can be displaced by excess radioinert ligand. The protein is prominently expressed in liver, kidney, and heart, but not in skeletal muscle. It is water soluble and found in the cytosol. Under denaturing conditions it has a molecular weight of 63 000 and appears on two-dimensional gels with an isoelectric point of 6.3. The protein's affinity for androgen is lower than that of the androgen receptor and it is about 100-fold more abundant than the receptor in the heart. Expression of the protein is not induced by androgen. The presence of this protein in testicular feminization (tfm) mice with a genetical defect of the androgen receptor rules out that it is the androgen receptor or a portion thereof. The biological role of this protein is not yet known.Key words: androgen, androgen receptor, heart, photolysis, steroid binding protein.

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