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

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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Sp1 up-regulates cAMP-response-element-binding protein expression during retinoic acid-induced mucous differentiation of normal human bronchial epithelial cells

Biochemical Journal ◽

10.1042/bj20070904 ◽

2008 ◽

Vol 410 (1) ◽

pp. 49-61 ◽

Cited By ~ 6

Author(s):

Jeong Soo Hong ◽

Seung-Wook Kim ◽

Ja Seok Koo

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Cell Differentiation ◽

Epithelial Cells ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Bronchial Epithelial ◽

Element Binding Protein ◽

Normal Human

CREB [CRE (cAMP-response element)-binding protein] is an important transcription factor that is differentially regulated in cells of various types. We recently reported that RA (retinoic acid) rapidly activates CREB without using RARs (RA receptors) or RXRs (retinoid X receptors) in NHTBE cells (normal human tracheobronchial epithelial cells). However, little is known about the role of RA in the physiological regulation of CREB expression in the early mucous differentiation of NHTBE cells. In the present study, we report that RA up-regulates CREB gene expression and that, using 5′-serial deletion promoter analysis and mutagenesis analyses, two Sp1 (specificity protein 1)-binding sites located at nt −217 and −150, which flank the transcription initiation site, are essential for RA induction of CREB gene transcription. Furthermore, we found that CREs located at nt −119 and −98 contributed to basal promoter activity. Interestingly, RA also up-regulated Sp1 in a time- and dose-dependent manner. Knockdown of endogenous Sp1 using siRNA (small interfering RNA) decreased RA-induced CREB gene expression. However, the converse was not true: knockdown of CREB using CREB siRNA did not affect RA-induced Sp1 gene expression. We conclude that RA up-regulates CREB gene expression during the early stage of NHTBE cell differentiation and that RA-inducible Sp1 plays a major role in up-regulating human CREB gene expression. This result implies that co-operation of these two transcription factors plays a crucial role in mediating early events of normal mucous cell differentiation of bronchial epithelial cells.

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Bile acids induce camp response element-binding protein (CREB) phosphorylation and CA2+ oscillations in rat biliary epithelial cells

Journal of Hepatology ◽

10.1016/s0168-8278(03)80352-5 ◽

2003 ◽

Vol 38 ◽

pp. 86 ◽

Cited By ~ 1

Author(s):

L. Wang ◽

J-F. Dufour

Keyword(s):

Epithelial Cells ◽

Bile Acids ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Creb Phosphorylation ◽

Biliary Epithelial Cells ◽

Element Binding Protein

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Prostaglandin E2InducesMUC8Gene Expression via a Mechanism Involving ERK MAPK/RSK1/cAMP Response Element Binding Protein Activation in Human Airway Epithelial Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m412722200 ◽

2004 ◽

Vol 280 (8) ◽

pp. 6676-6681 ◽

Cited By ~ 31

Author(s):

Kyou-Nam Cho ◽

Jae Young Choi ◽

Chang-Hoon Kim ◽

Seung Joon Baek ◽

Kwang Chul Chung ◽

...

Keyword(s):

Epithelial Cells ◽

Binding Protein ◽

Camp Response Element Binding ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Camp Response Element ◽

Response Element ◽

Protein Activation ◽

Human Airway ◽

Element Binding Protein

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cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Journal of Biological Chemistry ◽

10.1074/jbc.m109.001180 ◽

2009 ◽

Vol 284 (33) ◽

pp. 21810-21827 ◽

Cited By ~ 35

Author(s):

Krishnendu Chakraborty ◽

Palash Chandra Maity ◽

Alok Kumar Sil ◽

Yoshifumi Takeda ◽

Santasabuj Das

Keyword(s):

Epithelial Cells ◽

Antimicrobial Peptide ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Inducible Camp Early Repressor ◽

Element Binding Protein ◽

Peptide Expression ◽

Antimicrobial Peptide Expression

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Faculty Opinions recommendation of Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent memory?

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014814.194668 ◽

2003 ◽

Author(s):

Yadin Dudai

Keyword(s):

Synaptic Plasticity ◽

Binding Protein ◽

Camp Response Element Binding ◽

Pivotal Role ◽

Camp Response Element ◽

Response Element ◽

Hippocampal Synaptic Plasticity ◽

Element Binding Protein ◽

Hippocampus Dependent Memory

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Faculty Opinions recommendation of Nuclear inositol 1,4,5-trisphosphate receptors regulate local Ca2+ transients and modulate cAMP response element binding protein phosphorylation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027399.329527 ◽

2005 ◽

Author(s):

Thomas Cremer

Keyword(s):

Protein Phosphorylation ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Response Element ◽

Inositol 1,4,5 Trisphosphate ◽

Element Binding Protein

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Scutellarin Mitigates Cancer-Induced Bone Pain by Suppressing CaMKII/CREB Pathway in Rat Models

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.17:249-253 ◽

2019 ◽

Vol 17 (3) ◽

pp. 249-253

Author(s):

Liu Chenglong ◽

Liu Haihua ◽

Zhang Fei ◽

Zheng Jie ◽

Wei Fang

Keyword(s):

Protein Kinase ◽

Bone Pain ◽

Binding Protein ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Dependent Protein Kinase ◽

Response Element ◽

Protein Kinase Ii ◽

Element Binding Protein ◽

Dependent Protein

Cancer-induced bone pain is a severe and complex pain caused by metastases to bone in cancer patients. The aim of this study was to investigate the analgesic effect of scutellarin on cancer-induced bone pain in rat models by intrathecal injection of Walker 256 carcinoma cells. Mechanical allodynia was determined by paw withdrawal threshold in response to mechanical stimulus, and thermal hyperalgesia was indicated by paw withdrawal latency in response to noxious thermal stimulus. The paw withdrawal threshold and paw withdrawal latencies were significantly decreased after inoculation of tumor cells, whereas administration of scutellarin significantly attenuated tumor cell inoculation-induced mechanical and heat hyperalgesia. Tumor cell inoculation-induced tumor growth was also significantly abrogated by scutellarin. Ca2+/calmodulin-dependent protein kinase II is a multifunctional kinase with up-regulated activity in bone pain models. The activation of Ca2+/calmodulin-dependent protein kinase II triggers phosphorylation of cAMP-response element binding protein. Scutellarin significantly reduced the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein in cancer-induced bone pain rats. Collectively, our study demonstrated that scutellarin attenuated tumor cell inoculation-induced bone pain by down-regulating the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein. The suppressive effect of scutellarin on phosphorylated-Ca2+/calmodulin-dependent protein kinase II/phosphorylated-cAMP-response element binding protein activation may serve as a novel therapeutic strategy for CIBP management.

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