The human androgen receptor: structure/function relationship in normal and pathological situations.
Discrete functions have been attributed to precise regions of the human androgen receptor (hAR) by expression of deletion mutants in COS and HeLa cells. A large C-terminal domain constitutes the hormone-binding region and a central basis, cysteine-rich domain is responsible for DNA binding. In addition, separate domains responsible for transactivation and nuclear translocation have been identified. In LNCaP cells (a prostate tumor cell line) the hAR is a heterogeneous protein which is synthesized as a single 110 kDa protein, but becomes rapidly phosphorylated to a 112 kDa protein. Metabolic labeling experiments using radioactive orthophosphate also indicated that the hAR is a phosphoprotein. Structural analysis of the AR gene in LNCaP cells and in 46, XY-individuals displaying androgen insensitivity (AIS) has revealed several different point mutations. In LNCaP cells the mutation affects both binding specificity and transactivation by different steroids. In a person with complete AIS a point mutation was identified in the splice donor site of intron 4, which prevents normal splicing and activates a cryptic splice donor site in exon 4. The consequence is a functionally inactive AR protein due to an in-frame deletion in the steroid-binding domain. In two unrelated individuals with complete AIS, two different single nucleotide alterations in codon 686 (Asp) were found. Both mutations resulted in functionally inactive ARs due to rapidly dissociating hormone-AR complexes. It is concluded that the hAR is a heterogeneous phosphoprotein in which functional errors have a dramatic impact on phenotype and fertility of 46, XY-individuals.
Brinkmann
A O
AO
Department of Endocrinology and Reproduction, Erasmus University, Rotterdam, The Netherlands.
Jenster
G
G
Kuiper
G G
GG
Ris
C
C
van Laar
J H
JH
van der Korput
J A
JA
Degenhart
H J
HJ
Trifiro
M A
MA
Pinsky
L
L
Romalo
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002872:Chromosome Deletion; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D012016:Reference Values; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D014158:Transcription, Genetic; D014162:Transfection
D011944:Receptors, Androgen