Androgen receptor isoforms AR-A and AR-B display functional differences in cultured human bone cells and genital skin fibroblasts

被引:27
作者
Liegibel, UM
Sommer, U
Boercsoek, I
Hilscher, U
Bierhaus, A
Schweikert, HU
Nawroth, P
Kasperk, C
机构
[1] Univ Heidelberg, Dept Med, Div Osteol, D-69115 Heidelberg, Germany
[2] Univ Bonn, Dept Med, D-53111 Bonn, Germany
关键词
androgen receptor; protein isoforms; osteoblasts; fibroblasts; androgen response element; steroid;
D O I
10.1016/j.steroids.2003.08.016
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:1179 / 1187
页数:9
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