Han-Jung Lee

Recent advances in androgen receptor action

Androgens, principally testosterone and 5α-dihydrotestosterone, play critical roles in the development and growth of the male reproductive and nonreproductive systems. Their biological actions are mediated by the androgen receptor (AR), a ligand-dependent transcription factor, belonging to the nuclear receptor superfamily. These androgen-AR complexes interact with various factors (e.g. coactivators or corepressors) to modulate transcription of androgen target genes via specific DNA sequences. Many lines of evidence have also correlated AR with several mammalian disorders. Finally, recent advances in molecular biology have significantly impacted our knowledge of the role of AR in mammals. The aim of this review is to present recent emerging aspects of AR action.

Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily.

The human testicular receptor 2 (TR2) and TR4 orphan receptors are two evolutionarily related proteins belonging to the nuclear receptor superfamily. Numerous TR2 and TR4 variants and homologs have been identified from different species, including vertebrates (e.g. human, murine, rabbit, fish, and amphibian) and invertebrates (e.g. Drosophila, sea urchin, and nematode) since TR2 was initially isolated over a decade ago. Specific tissue distribution, genomic organization, and chromosomal assignment of both orphan receptors have been investigated. In order to reveal the physiological functions played by both TR2 and TR4, upstream modulators of TR2 and TR4 gene expression, their downstream target gene regulation, feedback mechanisms, and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been investigated. Studies summarized in the present report have provided unexpected insights into the TR2 and TR4 functions in a variety of biological processes. The essential and difficult tasks of identifying orphan receptor ligands, agonist/antagonist assignment, their physiological functions, and mechanisms of action will continue to challenge nuclear receptor researchers in the future.

THE FIRST DETECTION OF COMPLETE ANDROGEN INSENSITIVITY WITH NO MUTATION IN THE CODING SEQUENCE OF THE ANDROGEN RECEPTOR GENE

We have analyzed the entire nucleotide sequences of complementary DNAs of the androgen receptor gene in two siblings (patients 8044 and 8047) with complete androgen insensitivity. Plasma testosterone was in the normal male range, however, androgen binding capacity was undetectable as measured in skin fibroblasts in both patients. 5alpha-reductase activity was normal in both cases confirming that this enzyme is not involved in the mechanism of androgen insensitivity. Northern blot analysis indicated that mRNA of the AR was normal in size. In addition, no mutation was found in the entire nucleotide sequences of complementary DNAs of the androgen receptor gene. Together, our results reveal an unusual insight into the molecular basis of androgen resistance, and the molecular heterogeneity in this clinical spectrum.