Cell-specific inhibitory and stimulatory effects of Fos and Jun on transcription activation by nuclear receptors.
We investigated the effect of c-Fos and/or c-Jun co-expression on transcription activation by the progesterone (PR), glucocorticoid (GR) or androgen (AR) receptors using three different reporter genes and four different cell lines. We found that c-Fos could only inhibit, while c-Jun could either inhibit or further stimulate receptor-induced transcription. All these effects were receptor, promoter, and cell type specific, and, importantly, the steroid receptors had non-reciprocal effects on the transactivation ability of c-Jun in the presence or absence of c-Fos. Collectively, these results argue against heterodimer formation as a mechanism to explain the phenomena. Transactivation by the endogenous PR in T47D cells could be inhibited by increasing the intracellular c-Fos level with forskolin as well as by co-expressing c-Fos; no such effect was seen in MCF-7 cells. The inhibition by c-Fos of PR-induced transcription involves a competitive mechanism, which requires the presence of the intact c-Fos leucine zipper and is directed mainly at the transcription activation function (TAF) located in the PR and GR hormone binding domains (TAF-2). However, the co-expression of c-Fos did not alter the 'squelching/transcriptional interference' by the PR of estrogen receptor (ER)-induced transcription. Multiple mechanisms are discussed which may be involved in the crosstalk between the two signal transduction pathways.
Shemshedini
L
L
Laboratoire de Génétique Moléculaire des Eucaryotes, CNRS, Strasbourg, France.
Knauthe
R
R
Sassone-Corsi
P
P
Pornon
A
A
Gronemeyer
H
H
D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004247:DNA; D006367:HeLa Cells; D006801:Humans; D016350:Leucine Zippers; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000494:pharmacology; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D005576:Colforsin; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase