Androgen regulates the level and subcellular distribution of the AU-rich ribonucleic acid-binding protein HuR both in vitro and in vivo

HuR, a member of the ELAV family of AU-rich RNA-binding proteins, is presen t in a variety of tissues and is directly involved in stabilizing labile AU -rich messenger RNAs. We have found that treating the human HepG2 cell line with 10 nM dihydrotestosterone (DHT) for 48 h decreases the total level of HuR by 75%. DHT decreases both cytosolic and nuclear HuR levels in HepG2 c ells, but increases HuR levels in polyribosomes by 325%. In BALB/c mice, Hu R levels in the submaxillary salivary gland (SMG) and the kidney display a dramatic sexual dimorphism, but those in the spleen and thyroid do not. DHT (200 mug) causes total HuR levels in female SMG and kidney to fall progres sively, whereas, conversely, orchiectomy of males causes HuR levels to rise in these two tissues by 800% and 200%, respectively. As an internal contro l we probed the same blots for AUF1, a destabilizing AU-binding protein, an d confirmed our previous findings showing that the cytosolic p37 isoform of AUF1 shows the opposite responses of cytosolic HuR in the SMG, and that th e level of AUF1 in the kidney does not respond to DHT. In polyribosomes fro m female mouse SMG, HuR levels doubled after 6 h of DHT, but decreased by 8 0% after 24- and 48-h DHT treatment. Thus, the total level of HuR is regula ted in two different androgen-responsive systems, as is the shuttling of Hu R between different subcellular compartments. As AUF1 is responsive to andr ogen in the mouse SMG, but not in the kidney, tissue-specific posttranscrip tional regulation of AU-rich messenger RNA metabolism could be mediated in part by differential androgen-dependent regulation of HuR and AUF1.