Steroid regulation of receptor concentration and oncogene expression.
The DDT1MF-2 cell line was derived from an estrogen/androgen-induced tumor of the hamster ductus deferens. This cell line contains receptors for both androgens and glucocorticoids and its proliferation is differentially sensitive to these classes of steroids. Androgens stimulate cell growth dramatically and augment intracellular androgen receptors, whereas glucocorticoids inhibit growth and prevent androgen receptor augmentation. Androgen receptor augmentation occurs by an androgen-dependent increase in receptor half-life and an increase in the rate of synthesis. Glucocorticoids, in the presence of androgens, reduce both the half-life and the rate of synthesis of androgen receptors. For comparison purposes, a glucocorticoid-resistant mutant (DDT1MF-2-GR) of this cell line has been developed. Unlike the wild type, in this variant glucocorticoids neither arrest cell growth nor inhibit androgen receptor augmentation. Glucocorticoids block growth of the wild type in the G1-phase of the cell cycle. This event can be overcome either by addition of exogenous platelet-derived growth factor (PDGF) or by the addition of concentrated conditioned medium from nonglucocorticoid-treated cells, however, androgen receptor augmentation remains inhibited. The reduced production of PDGF-like growth factors in the presence of glucocorticoids appears to be the result of a decrease in production of mature mRNA with homology to v-sis (the viral oncogene coding for PDGF-like proteins). The level of regulation appears to be posttranscriptional and does not occur in the DDT1MF-2-GR cells. Thus glucocorticoids regulate the autocrine growth of the DDT1MF-2 cells by a mechanism that can be uncoupled from the regulation of androgen receptor augmentation.
Smith
R G
RG
Nag
A
A
Syms
A J
AJ
Norris
J S
JS
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D005834:Genital Neoplasms, Male / Q000032:analysis / Q000235:genetics / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D009857:Oncogenes; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000494:pharmacology; D012313:RNA / Q000032:analysis; D011944:Receptors, Androgen / Q000032:analysis*; D011965:Receptors, Glucocorticoid / Q000032:analysis*; D014158:Transcription, Genetic / Q000187:drug effects
D000728:Androgens; D005938:Glucocorticoids; D010982:Platelet-Derived Growth Factor; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D012313:RNA