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Vol. 17, Issue 2, 566-575, February 2006

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Nonclassical Action of Retinoic Acid on the Activation of the cAMP Response Element-binding Protein in Normal Human Bronchial Epithelial Cells

Sita Aggarwal ^* , Seung-Wook Kim ^* , Kyounga Cheon ^*, Fazal H. Tabassam ^*, Joo-Heon Yoon , and Ja Seok Koo ^*

^* Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 120-752, Korea

Submitted June 10, 2005; Revised October 7, 2005; Accepted November 2, 2005
Monitoring Editor: J. Silvio Gutkind

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.

Abbreviations used: CREB, cAMP response element-binding protein; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; NHTBE, normal human tracheobronchial epithelium; pCREB, phosphorylated cAMP response element-binding protein; PKA, protein kinase A; RA, retinoic acid; RARE, retinoic acid response elements; RAR, retinoic acid receptor; RXR, retinoid X receptor; RSK, p90 ribosomal S6 kinase; siRNA, small interfering RNA.

These authors contributed equally to this work.

Address correspondence to: Ja Seok Koo (jskoo{at}mdanderson.org).

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