Androgens inhibit androgen receptor promoter activation in motor neurons
Abstract
The androgen receptor (AR), a ligand-activated transcription factor, has been found mutated in several human diseases. While some mutations reduce, others potentiate AR functions generating different endocrine dysfunctions. A peculiar AR mutation, the CAG-repeat expansion encoding the AR-polyglutamine (polyQ) tract, generates a neurotoxic gain-of-function(s) in this mutant AR (ARpolyQ). This leads to the motor neuronal disease Spinal and Bulbar Muscular Atrophy (SBMA), in which the transcriptional AR down-regulation might have beneficial impacts. We thus analysed the AR-promoter/5'-UTR activation and androgenic regulation, demonstrating that its constitutive activity is considerably high in motor neurons (NSC34). Testosterone, dihydrotestosterone (DHT), but not estradiol, inhibited AR promoter activation. Thus AR establishes a negative control on its own functions, in opposition to that described on classical androgen-responsive elements (ARE) of the AR gene. The AR/DNA interaction is required for this action, since DHT does not inhibit AR expression in presence of an AR (AR_DeltaPhe581) lacking DNA binding activity. The minimal inhibitory region spans from -740/+570 bp, where "in silico" analysis showed a putative AR binding site; deletion studies excluded that this ARE may be involved in this inhibition. A similar effect of DHT has also been observed in AR negative prostate cancer DU145 cell line transfected with the AR. Moreover, androgens down-regulate the expression of…
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