Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model
| Autor: | Udo Moehren, Guy Verrijdt, Leen Callewaert, Kris Schauwaers, Karel De Gendt, Guido Verhoeven, Philippa T. K. Saunders, Johannes V. Swinnen, Annemie Haelens, Frank Claessens, Nina Atanassova |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Transcriptional Activation medicine.drug_class medicine.medical_treatment Molecular Sequence Data Proteinase Inhibitory Proteins Secretory Cell Count Biology Response Elements Transfection Androgen receptor binding Mice Glucocorticoid receptor Testis medicine Animals Humans Amino Acid Sequence RNA Messenger Receptor Transcription factor Homeodomain Proteins Multidisciplinary Reproduction Body Weight Proteins Zinc Fingers Biological Sciences Androgen Phenotype Molecular biology Cell biology Androgen receptor Steroid hormone Receptors Androgen Models Animal Androgens Female HeLa Cells Protein Binding Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:4961-4966 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Androgens influence transcription of their target genes through the activation of the androgen receptor (AR) that subsequently interacts with specific DNA motifs in these genes. These DNA motifs, called androgen response elements (AREs), can be classified in two classes: the classical AREs, which are also recognized by the other steroid hormone receptors; and the AR-selective AREs, which display selectivity for the AR. For in vitro interaction with the selective AREs, the androgen receptor DNA-binding domain is dependent on specific residues in its second zinc-finger. To evaluate the physiological relevance of these selective elements, we generated a germ-line knockin mouse model, termed SPARKI (SPecificity-affecting AR KnockIn), in which the second zinc-finger of the AR was replaced with that of the glucocorticoid receptor, resulting in a chimeric protein that retains its ability to bind classical AREs but is unable to bind selective AREs. The reproductive organs of SPARKI males are smaller compared with wild-type animals, and they are also subfertile. Intriguingly, however, they do not display any anabolic phenotype. The expression of two testis-specific, androgen-responsive genes is differentially affected by the SPARKI mutation, which is correlated with the involvement of different types of response elements in their androgen responsiveness. In this report, we present the first in vivo evidence of the existence of two functionally different types of AREs and demonstrate that AR-regulated gene expression can be targeted based on this distinction. |
| Databáze: | OpenAIRE |
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