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Title: A physiological role for androgen actions in the absence of androgen receptor DNA binding activity.
Austin Authors: Pang, Tammy P S;Clarke, Michele V;Ghasem-Zadeh, Ali ;Lee, Nicole K L;Davey, Rachel A;MacLean, Helen E
Affiliation: Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Vic. 3084, Australia
Issue Date: 22-Aug-2011
Publication information: Molecular and Cellular Endocrinology 2011; 348(1): 189-97
Abstract: We tested the hypothesis that androgens have physiological actions via non-DNA binding-dependent androgen receptor (AR) signaling pathways in males, using our genetically modified mice that express a mutant AR with deletion of the 2nd zinc finger of the DNA binding domain (AR(ΔZF2)) that cannot bind DNA. In cultured genital skin fibroblasts, the mutant AR(ΔZF2) has normal ligand binding ability, phosphorylates ERK-1/2 in response to 1 min DHT treatment (blocked by the AR antagonist bicalutamide), but has reduced androgen-dependent nuclear localization compared to wildtype (WT). AR(ΔZF2) males have normal baseline ERK-1/2 phosphorylation, with a 1.5-fold increase in Akt phosphorylation in AR(ΔZF2) muscle vs WT. To identify physiological actions of non-DNA binding-dependent AR signaling, AR(ΔZF2) males were treated for 6 weeks with dihydrotestosterone (DHT). Cortical bone growth was suppressed by DHT in AR(ΔZF2) mice (6% decrease in periosteal and 7% decrease in medullary circumference vs untreated AR(ΔZF2) males). In conclusion, these data suggest that non-DNA binding dependent AR actions suppress cortical bone growth, which may provide a mechanism to fine-tune the response to androgens in bone.
Gov't Doc #: 21872641
DOI: 10.1016/j.mce.2011.08.017
Journal: Molecular and cellular endocrinology
Type: Journal Article
Subjects: Androgens.pharmacology.physiology
Cell Nucleus.metabolism
Femur.anatomy & histology.drug effects.metabolism
Gene Expression
Gene Expression Regulation
MAP Kinase Signaling System
Mice, Inbred C57BL
Models, Biological
Muscle, Skeletal.metabolism
Organ Specificity
Protein Binding
Protein Transport
Receptors, Androgen.genetics.metabolism
Response Elements
Sequence Deletion
Subcutaneous Fat.metabolism
Appears in Collections:Journal articles

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