Androgen receptor isoforms AR-A and AR-B display functional differences in cultured human bone cells and genital skin fibroblasts.
Two isoforms of the androgen receptor (AR-A and AR-B), differing by a lack of the first 187 amino acids in the NH2-terminal transactivation domain of AR-A, are expressed in connective tissue and bone. Transient transfections of normal human osteoblastic cells (HOB) and of genital skin fibroblasts defective in AR (GSF-540) were utilized to compare the functional properties of AR isoforms in mesenchymal tissues. Overexpression of AR-B or AR-A did not significantly affect type I collagen secretion. However, overexpression of AR-B (but not AR-A) restored androgen-dependent DNA synthesis in AR-defective fibroblasts and increased DHT-mediated DNA synthesis three-fold in osteoblastic cells. Overexpression of AR-A did not affect DHT action but reduced DHT-dependent DNA synthesis when transfected together with AR-B. The need for an NH2-terminal sequence of the AR for complete receptor function was demonstrated using electrophoretic mobility shift assay. A peptide coding for the amino terminus of the complete AR was able to decrease the binding affinity of AR-B and increase the binding affinity of AR-A to the androgen response element. Our results suggest that AR-A lacks the ability to stimulate cell proliferation possibly due to reduced binding of AR co-activating proteins to the truncated N-terminal transactivation domain rather than due to impaired stability of the AR-A isoform.
Liegibel
Ute M
UM
Division of Osteology, Department of Medicine, Ruprecht-Karls-University, Luisenstr. 5, 69115 Heidelberg, Germany.
Sommer
Ulrike
U
Boercsoek
Irma
I
Hilscher
Ulrike
U
Bierhaus
Angelika
A
Schweikert
Hans Udo
HU
Nawroth
Peter
P
Kasperk
Christian
C
D000328:Adult; D000728:Androgens / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D014644:Genetic Variation; D005835:Genitalia / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D020033:Protein Isoforms / Q000502:physiology; D011944:Receptors, Androgen / Q000502:physiology*; D012867:Skin / Q000378:metabolism*; D013577:Syndrome; D015533:Transcriptional Activation
D000728:Androgens; D024042:Collagen Type I; D020033:Protein Isoforms; D011944:Receptors, Androgen; D004247:DNA