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Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes

Oncogene volume 20, pages 5164–5172 (2001)Cite this article

Abstract

It has been shown that UVB irradiation induces expression of COX-2 and up-regulation of COX-2 plays a functional role in UVB tumor promotion. In this study, we examined the cis-elements in the human COX-2 promoter that may be responsible for the UVB induction of COX-2. Analyses with the COX-2 promoter region revealed that the cyclic AMP responsive element near the TATA box was essential for both basal and UVB induced COX-2 expression. This was further supported by studies using a dominant negative mutant of CREB, which strongly inhibited the activity of COX-2 promoter. Electrophoretic mobility shift assays indicated that CREB and ATF-1 were the major proteins binding to the COX-2 CRE. CREB and ATF-1 were phosphorylated upon UVB treatment, and SB202190, a p38 MAPK inhibitor, decreased the phosphorylation of CREB/ATF-1 and suppressed COX-2 promoter activity. In contrast, treatment with forskolin, an activator of adenylyl cyclase, led to phosphorylation of CREB and ATF-1 and activation of COX-2 promoter. Finally, enhanced binding of phospho-CREB/ATF-1 to the COX-2 CRE was observed after UVB induction. Thus, one signaling pathway for UVB induction of human COX-2 involves activation of p38, subsequent phosphorylation of CREB/ATF-1, and activation of the COX-2 CRE through enhanced binding of phosphorylated CREB/ATF-1.

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Abbreviations

UVB:

ultraviolet B

COX-2:

cyclooxygenase-2

COX-1:

cyclooxygenase-1

CRE:

cyclic AMP responsive element

CREB:

CRE binding protein

AP-1:

activator protein-1

MAP:

mitogen-activated protein

ERK:

extracellular signal-regulated protein kinase

p38:

p38 MAP kinase

ATF-1:

activating transcription factor

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Acknowledgements

We thank Suzanne Stratton for critical review of the manuscript and many suggestions. We are also grateful for the invaluable secretary assistance of Anne Cione. This work was support in part by NIH grant CA27502.

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Authors and Affiliations

  1. Department of Radiation Oncology, Arizona Cancer Center, College of Medicine, The University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, Arizona, USA

    Qingbo Tang, Weixing Chen, Melissa S Gonzales, Joanne Finch & G Tim Bowden

  2. The Department of Pharmacology, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, 565-8565, Osaka, Japan

    Hiroyasu Inoue

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  1. Qingbo Tang
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Correspondence to G Tim Bowden.

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Tang, Q., Chen, W., Gonzales, M. et al. Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes. Oncogene 20, 5164–5172 (2001). https://doi.org/10.1038/sj.onc.1204667

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