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All-trans-retinoic acid inhibits Jun N-terminal kinase-dependent signaling pathways
H Y Lee1, G L Walsh, M I Dawson
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. The signaling pathways through which retinoids mediate this effect have not been defined. Normal HBE cell growth is stimulated by treatment with a variety of growth factors that increase mitogen-activated protein (MAP) activity. In this study, we examined MAP kinase-dependent pathways as potential targets of retinoid signaling and the role of MAP kinases in retinoid-induced c-fos gene regulation. All-trans-retinoic acid (t-RA) inhibited Jun N-terminal kinase (JNK) and, to a lesser extent, extracellular signal-regulated kinase activity in normal HBE cells. t-RA reduced c-fos mRNA and protein levels by decreasing c-fos gene transcription. The c-fos promoter was activated by co-transfection with a constitutively active JNK kinase (SEK)-1 and suppressed by a dominant negative JNK kinase kinase (MEKK)-1. Furthermore, c-fos expression was inhibited by agonists of retinoic acid receptors (RARs) or retinoid X receptors (RXRs), and suppression of c-fos promoter activity by t-RA was abrogated by treatment with antagonists of RAR-alpha or of all the RXRs. These findings provide the first evidence that t-RA inhibits JNK activity and demonstrate a potential role of JNK-dependent pathways in the suppression of c-fos expression by t-RA. Furthermore, c-fos expression was inhibited through activation of RAR- and RXR-dependent signaling pathways. In light of the growth activation induced by JNK/SEK-dependent pathways in a variety of cells, these data support further investigation into the role of JNK-dependent signaling in the growth-suppressive effects of retinoids.
Insights
Retinoids inhibit bronchial cell growth by suppressing Jun N-terminal kinase (JNK) activity and c-fos gene expression. This study reveals retinoid signaling pathways targeting JNK, impacting cell growth regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Retinoids, such as retinol and retinoic acid derivatives, are known to inhibit normal human bronchial epithelial (HBE) cell growth.
- The specific signaling pathways mediating retinoid effects on cell growth remain largely undefined.
- Mitogen-activated protein (MAP) kinase activity is crucial for growth factor-stimulated HBE cell proliferation.
Purpose of the Study:
- To investigate MAP kinase-dependent pathways as targets of retinoid signaling.
- To elucidate the role of MAP kinases in retinoid-induced c-fos gene regulation.
- To understand how retinoids influence bronchial epithelial cell growth.
Main Methods:
- Assessed the effect of all-trans-retinoic acid (t-RA) on Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activity in HBE cells.
- Quantified c-fos mRNA and protein levels following t-RA treatment.
- Utilized promoter assays with JNK kinase (SEK)-1 and JNK kinase kinase (MEKK)-1 constructs.
- Examined the role of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) using agonists and antagonists.
Main Results:
- All-trans-retinoic acid (t-RA) inhibited both JNK and ERK activity in HBE cells.
- t-RA significantly reduced c-fos mRNA and protein levels by suppressing gene transcription.
- Constitutively active SEK-1 activated the c-fos promoter, while dominant-negative MEKK-1 suppressed it.
- Agonists of RARs and RXRs inhibited c-fos expression, and t-RA's suppression was blocked by antagonists of RAR-alpha and RXRs.
Conclusions:
- This study provides the first evidence that t-RA inhibits JNK activity in HBE cells.
- JNK-dependent pathways play a significant role in retinoid-mediated suppression of c-fos expression.
- Retinoid-induced growth suppression in bronchial epithelial cells involves RAR- and RXR-dependent signaling pathways impacting JNK/c-fos.