Differential modulation of gene induction by glucocorticoids and antiglucocorticoids in rat hepatoma tissue culture cells.
Studies of glucocorticoid and antiglucocorticoid induction of tyrosine aminotransferase (TAT) in two rat hepatoma cell lines (Fu5-5 and HTC) are described. These studies revealed several phenomena that are not consistent with the current models of steroid hormone action: (a) TAT induction occurred at glucocorticoid levels below those required for comparable receptor occupancy in Fu5-5, but not in HTC, cells; (b) the ability of antiglucocorticoids to induce TAT is higher in Fu5-5 than in HTC cells; (c) the values of the amount of TAT agonist activity with the antiglucocorticoid dexamethasone 21-mesylate and of log10 of the dexamethasone concentration required for half-maximal induction of TAT were not constant over time but varied in a linear, reciprocal manner. This modulation was seen for several glucocorticoids and antiglucocorticoids at the level of both TAT enzyme and mRNA but not for two other glucocorticoid inducible genes in the same cells. These results, plus the fact that a similar difference in the concentration required for half-maximal TAT induction in Fu5-5 cells was seen for both glucocorticoids and cyclic AMP, argue that the modulation occurs at some point distal to receptor-steroid complex binding to the biologically active nuclear sites but proximal to translation of TAT mRNA. In order to explain these results, it is pointed out that models involving second messengers are entirely appropriate for steroid hormone action. The participation of a modulated trans-acting factor in such a model may explain the above results.
Simons
S S
SS
Laboratory of Analytical Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
Mercier
L
L
Miller
N R
NR
Miller
P A
PA
Oshima
H
H
Sistare
F D
FD
Thompson
E B
EB
Wasner
G
G
Yen
P M
PM
D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000032:analysis; D015533:Transcriptional Activation; D014444:Tyrosine Transaminase / Q000235:genetics*
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D000242:Cyclic AMP; D014444:Tyrosine Transaminase; C031710:dexamethasone 21-methanesulfonate