Role of transcription factors in the age-dependent regulation of the androgen receptor gene in rat liver.

Abstract

Androgen receptor (AR) is a ligand-activated transcription factor involved in mediating male reproductive functions. The high expression of the AR gene in target tissues of young-adult animals is generally followed by an age-dependent decline during the postreproductive life. The liver of male rats shows about a 50- to 100-fold decline in androgen sensitivity during old age due to a concomitant decline of the AR gene expression. This decline corresponds to changes in the nuclear level of several transcription factors that bind to the AR gene promoter. The positively acting factors that control the AR gene and undergo an age-dependent decline include the age-dependent transcription factor (ADF), Sp1 and the serum response factor (SRF). Nuclear factor kappa B, which functions as a negative regulator of the AR promoter, undergoes about a 10-fold increase during the age-dependent loss of the hepatic androgen sensitivity. Additionally, AP3, which can potentially function as a regulator of the AR gene, shows a marked increase during old age. Thus, a coordinated interaction among a number of positive and negative regulators appears to guide the downregulation of the AR gene during aging.