Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 17, Issue 2, Pages 566-575Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E05-06-0519
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Funding
- NCI NIH HHS [CA-16672, R01 CA126801, P30 CA016672] Funding Source: Medline
- NHLBI NIH HHS [R01-HL-077556, R01 HL077556] Funding Source: Medline
- NIEHS NIH HHS [K22-ES-000362, K22 ES000362] Funding Source: Medline
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Vitamin A (retinol) is essential for normal regulation of cell growth and differentiation. We have shown that the retinol metabolite retinoic acid (RA) induces mucous cell differentiation of normal human tracheobronchial epithelial (NHTBE) cells. However, early biological effects of RA in the differentiation of bronchial epithelia are largely unknown. Here, we showed that RA rapidly activated cAMP response element-binding protein (CREB). However, RA did not use the conventional retinoic acid receptor (RAR)/retinoid X receptor (RXR) to activate CREB. RA activated CREB in NHTBE and H1734 cells in which RARs/RXR were silenced with small interfering RNA (siRNA) targeting RAR/RXR expression or deactivated by antagonist. Inhibition of protein kinase C (PKC) or extracellular regulated kinase (ERK1/2) blocked the RA-mediated activation of CREB. In addition, depletion of p90 ribosomal S6 kinase (RSK) via siRSK1/2 completely abolished the activation, suggesting that PKC, ERK, and RSK are required for the activation. Altogether, this study provides the first evidence that RA rapidly activates CREB transcription factor via PKC, ERK, and RSK in a retinoid receptor-independent manner in normal bronchial epithelial cells. This noncanonical RA signaling pathway may play an important role in mediating early biological effects in the mucociliary differentiation of bronchial epithelia.
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