The human androgen receptor: domain structure, genomic organization and regulation of expression.
The domain structure and the genomic organization of the human androgen receptor (hAR) has been studied after molecular cloning and characterization of cDNA and genomic DNA encoding the hAR. The cDNA sequence reveals an open reading frame of 2751 nucleotides encoding a protein of 917 amino acids with a calculated molecular mass of 98,845 D. The N-terminal region of the hAR is characterized by a high content of acidic amino acid residues and by several homopolymeric amino acid stretches. The DNA-binding domain showed a high homology with the DNA-binding domain of the human glucocorticoid receptor (hGR) and the human progesterone receptor (hPR). The predominantly hydrophobic steroid binding domain of the hAR is 50-55% homologous with the ligand binding domains of the hGR and hPR. Transient expression of recombinant AR cDNA in COS-cells resulted in the production of a 110 kDa protein with the expected binding specificity of androgen receptors. Co-transfection with a reporter-gene construct [CAT(chloramphenicol acetyl transferase) under direction of the androgen regulated MMTV-promoter] showed that the protein is functionally active with respect to transcription regulation. In the LNCaP prostate carcinoma cell line two major (11 and 8 kb) and one minor (4.7 kb) mRNA species can be found which can be down-regulated by androgens. The hAR protein coding region was shown to be divided over eight exons with an organization similar to that of the progesterone and oestrogen receptor. The sequence encoding the N-terminal domain was found in one large exon. The two DNA-binding fingers were encoded by two small exons; the information for the androgen-binding domain was found to be distributed over five exons. Southern blot analysis of genomic DNA revealed that the hAR is encoded by one single gene, which is situated on the X-chromosome.
Brinkmann
A O
AO
Department of Biochemistry, Erasmus University, Rotterdam, The Netherlands.
Faber
P W
PW
van Rooij
H C
HC
Kuiper
G G
GG
Ris
C
C
Klaassen
P
P
van der Korput
J A
JA
Voorhorst
M M
MM
van Laar
J H
JH
Mulder
E
E
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015183:Restriction Mapping; D014162:Transfection
D011944:Receptors, Androgen; D004247:DNA