Regulation of mucin gene expression by CREB via a nonclassical retinoic acid signaling pathway.
Vitamin A and its metabolite retinoic acid (RA) are essential elements for normal lung development and the differentiation of lung epithelial cells. We previously showed that RA rapidly activated cyclic AMP response element-binding protein (CREB) in a nonclassical manner in normal human tracheobronchial epithelial (NHTBE) cells. In the present study, we further demonstrated that this nonclassical signaling of RA on the activation of CREB plays a critical role in regulating the expression of airway epithelial cell differentiation markers, the MUC2, MUC5AC, and MUC5B genes. We found that RA rapidly activates the protein kinase Calpha isozyme and transmits the activation signal to CREB via the Raf/MEK/extracellular signal-regulated kinase/p90 ribosomal S6 kinase (RSK) pathway. Activated RSK translocated from the cytoplasm to the nucleus, where it phosphorylates CREB. Activated CREB then binds to a cis-acting replication element motif on the promoter (at nucleotides [nt] -878 to -871) of the MUC5AC gene. The depletion of CREB using small interfering RNA abolished not only the RA-induced MUC5AC but also RA-induced MUC2 and MUC5B. Taken together, our findings demonstrate that CREB activation via this nonclassical RA signaling pathway may play an important role in regulating the expression of mucin genes and mediating the early biological effects of RA during normal mucous differentiation in NHTBE cells.
Kim
Seung-Wook
SW
Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Hong
Jeong Soo
JS
Ryu
Seung-Hee
SH
Chung
Wen-Cheng
WC
Yoon
Joo-Heon
JH
Koo
Ja Seok
JS
D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D055271:Mucin 5AC; D055262:Mucin-2; D055257:Mucin-5B; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology; D047488:Retinoid X Receptors / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D007527:Isoenzymes; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D055257:Mucin-5B; D009077:Mucins; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014212:Tretinoin; D019893:Ribosomal Protein S6 Kinases; D048490:raf Kinases; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases