The human androgen receptor: Structure/function relationship in normal and pathological situations

• Published in: Journal of steroid biochemistry and molecular biology Vol. 41; no. 3; pp. 361 - 368
• Main Authors: Brinkmann, A.O., Jenster, G., Kuiper, G.G.J.M., Ris, C., van Laar, J.H., van der Korput, J.A.G.M., Degenhart, H.J., Trifiro, M.A., Pinsky, L., Romalo, G., Schweikert, H.U., Veldscholte, J., Mulder, E., Trapman, J.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Oxford Elsevier Ltd 01.03.1992; Elsevier Science
• Subjects: Amino Acid Sequence; androgens; Animals; Base Sequence; Biological and medical sciences; Cell Line; Cell receptors; Cell structures and functions; Chromosome Deletion; Fundamental and applied biological sciences. Psychology; HeLa Cells; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Humans; Male; man; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis; Phosphorylation; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Processing, Post-Translational; receptors; Receptors, Androgen - genetics; Receptors, Androgen - isolation & purification; Receptors, Androgen - metabolism; Reference Values; Regulatory Sequences, Nucleic Acid; Restriction Mapping; RNA Splicing; structure-activity relationships; Transcription, Genetic; Transfection; Human; Androgen; Sex steroid hormone; Hormonal receptor
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/0960-0760(92)90362-M

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.