All-trans-retinoic acid inhibits Jun N-terminal kinase-dependent signaling pathways.
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.
Lee
H Y
HY
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Walsh
G L
GL
Dawson
M I
MI
Hong
W K
WK
Kurie
J M
JM
D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*
D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases