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Stat3 enhances transactivation of steroid hormone receptors
Fernando De Miguel1, Soo Ok Lee, Sergio A Onate
1Department of Medicine and Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. allen.gao@roswellpark.org
Abstract:
BACKGROUND: Steroid hormone receptors (SHRs) are members of the superfamily of ligand-activated transcription factors that regulate many biological processes. Co-regulators act as bridging molecules between the SHR and general transcription factors to enhance transactivation of target genes. Previous studies demonstrated that Stat3 is constitutively activated in prostate cancer and can enhance prostate specific antigen (PSA) expression and promote androgen independent growth. In this study, we investigate whether Stat3 can enhance steroid hormone receptors activation. METHODS: CV-1 cells in which plasmids expressing androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR) or estrogen receptor (ER) were cotransfected with a constitutively active STAT3 mutant. RESULTS: Stat3 stimulates the transcriptional activity of all four SHR tested, AR, GR, PR and ER, in a hormone-dependent manner. Stat3 acts in a synergistic fashion with other coactivators such as SRC-1, pCAF, CBP, and TIF-2 on the transcriptional activity of these SHR. In addition, Stat3 significantly enhanced the sensitivity of androgen receptor in response to androgen. STAT3 did not affect the specificity of AR for other steroid hormones other than androgen or binding of AR to other hormone responsive elements. CONCLUSIONS: These findings suggest that Stat3 can enhance the transactivation of AR, GR, PR and ER, and activated Stat3 could have a role in the development or progression of a hypersensitive AR.
Insights
Signal transducer and activator of transcription 3 (Stat3) enhances the activity of steroid hormone receptors (SHRs), including the androgen receptor (AR). Activated Stat3 may play a role in prostate cancer progression by increasing AR sensitivity.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- Steroid hormone receptors (SHRs) are crucial ligand-activated transcription factors regulating diverse biological processes.
- Co-regulators bridge SHRs and transcription factors, enhancing gene transactivation.
- Constitutive Stat3 activation is observed in prostate cancer, promoting PSA expression and androgen-independent growth.
Purpose of the Study:
- To investigate the potential of Stat3 in enhancing steroid hormone receptor activation.
- To determine if Stat3 influences the transcriptional activity of key SHRs.
Main Methods:
- CV-1 cells were utilized for co-transfection experiments.
- Plasmids expressing androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and estrogen receptor (ER) were co-transfected with a constitutively active STAT3 mutant.
Main Results:
- Stat3 significantly stimulated the hormone-dependent transcriptional activity of AR, GR, PR, and ER.
- Stat3 synergized with known coactivators (SRC-1, pCAF, CBP, TIF-2) to enhance SHR activity.
- Stat3 markedly increased androgen receptor sensitivity to androgens without altering hormone or DNA binding specificity.
Conclusions:
- Stat3 enhances the transactivation of AR, GR, PR, and ER.
- Activated Stat3 may contribute to the development or progression of hypersensitive androgen receptor signaling.