Differential induction of pS2 and cathepsin D mRNAs by structurally altered estrogens.
The influence of structural alterations to the estradiol-17 beta (E2) molecule on the induction of pS2 and Cathepsin D (Cath D) mRNAs has been examined by Northern analysis of RNA extracted from MCF-7 cells. Exposure of cultures to estratriene did not affect the level of expression of these estrogen-responsive genes. Addition of one hydroxyl group to estratriene at either of the hydroxylated positions of E2 (3-phenolic or 17 beta) yielded monohydroxyestrogens which stimulated the synthesis of Cath D and pS2 mRNAs to a level comparable to that induced by 10(-10) M E2 and displayed a decrease in activity at the higher concentrations (10(-8) - 10(-7) M) similar to that of the parent estrogen. Both of these genes were induced maximally by estrogens with D-ring alterations. Movement of the phenolic hydroxyl group of E2 to other positions on the A-ring yielded ligands which were highly discriminatory in the induction of these messages. 1-Hydroxyestratrien-17 beta-ol was capable of stimulating maximal synthesis of both pS2 and Cath D mRNAs when added to cultures of MCF-7 cells at a concentration of 10(-8) M. Placement of the phenolic hydroxyl at position 4 greatly diminished the induction of these two estrogen-responsive genes. On the other hand, positioning the A-ring hydroxyl group on carbon 2 yielded a ligand which brought about the induction of one gene (pS2) but was marginally effective in the induction of Cath D mRNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Pilat
M J
MJ
Department of Biochemistry, Wayne State University School of Medicine, Detroit, Michigan 48201.
Hafner
M S
MS
Kral
L G
LG
Brooks
S C
SC
D001483:Base Sequence; D002402:Cathepsin D / Q000235:genetics*; D004247:DNA; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000235:genetics*; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000187:drug effects; D014158:Transcription, Genetic; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D004247:DNA; D002402:Cathepsin D