Cell-specific inhibitory and stimulatory effects of Fos and Jun on transcription activation by nuclear receptors

EMBO J. 1991 Dec;10(12):3839-49.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Colforsin / pharmacology
  • DNA
  • HeLa Cells
  • Humans
  • Leucine Zippers
  • Molecular Sequence Data
  • Mutation
  • Plasmids
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / pharmacology
  • Proto-Oncogene Proteins c-jun / genetics*
  • Proto-Oncogene Proteins c-jun / pharmacology
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / metabolism
  • Receptors, Glucocorticoid / drug effects
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / metabolism
  • Receptors, Steroid / drug effects
  • Receptors, Steroid / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation*
  • Transfection

Substances

  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, Androgen
  • Receptors, Glucocorticoid
  • Receptors, Progesterone
  • Receptors, Steroid
  • Colforsin
  • DNA
  • Chloramphenicol O-Acetyltransferase