Intracellular inhibition of chromatin binding and transformation of androgen receptor by 3'-deoxyadenosine.
Incubation of minced rat ventral prostate with 3'-deoxyadenosine (3'-dA) prior to labeling with the androgen, tritiated 7 alpha, 17 alpha-dimethyl-19-nortestosterone, reduced the level of androgen receptor bound to chromatin and increased the level of cytosolic androgen receptor and the fraction of cytosolic androgen receptor that did not bind to DNA. This effect was specific for 3'-dA and not mimicked by adenosine, 2'-deoxy-adenosine, cytidine, guanosine, or uridine. Adenosine was a competitive inhibitor of the 3'-dA effect. Labeled cytosolic androgen receptor from 3'-dA-treated prostate had properties that were similar to those exhibited by untransformed androgen receptor from prostate cytosol prepared in the presence of Na2MoO4, an inhibitor of receptor transformation in cell-free systems. Both androgen receptors had sedimentation coefficients of 8-9 S in low-salt gradients, did not bind to DNA tightly, and had a high affinity for DEAE-cellulose. The 3'-dA effect on these properties was not observed if androgen receptor from 3'-dA-treated prostate was isolated on high-salt gradients. These findings show that androgen receptor transformation does take place in intact prostate cells and suggest that 3'-dA inhibits chromatin binding of androgen receptor by interfering with androgen receptor transformation. The transformation process appears to involve removal of components from androgen receptor. Since 3'-dA is a potent inhibitor of the synthesis, polyadenylation, and nucleocytoplasmic transport of RNA, the 3'-dA effect may indicate a role for RNA in the mechanism of receptor transformation in intact target cells.
Hiipakka
R A
RA
Ben May Institute, University of Chicago, Illinois 60637.
Liao
S T
ST
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D003839:Deoxyadenosines / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009919:Orchiectomy; D011467:Prostate / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*
D002843:Chromatin; D003839:Deoxyadenosines; D011944:Receptors, Androgen; D000241:Adenosine