p27 suppresses cyclooxygenase-2 expression by inhibiting p38β and p38δ-mediated CREB phosphorylation upon arsenite exposure.

Abstract

p27 is a cyclin-dependent kinase (CDK) inhibitor that suppresses a cell's transition from G0 to S phase, therefore acting as a tumor suppressor. Our most recent studies demonstrate that upon arsenite exposure, p27 suppresses Hsp27 and Hsp70 expressions through the JNK2/c-Jun- and HSF-1-dependent pathways, suggesting a novel molecular mechanism underlying the tumor suppressive function of p27 in a CDK-independent manner. We found that p27-deficiency (p27-/-) resulted in the elevation of cyclooxygenase-2 (COX-2) expression at transcriptional level, whereas the introduction of p27 brought back COX-2 expression to a level similar to that of p27+/+ cells, suggesting that p27 exhibits an inhibitory effect on COX-2 expression. Further studies identified that p27 inhibition of COX-2 expression was specifically due to phosphorylation of transcription factor cAMP response element binding (CREB) phosphorylation mediated by p38β and p38δ. These results demonstrate a novel mechanism underlying tumor suppression effect of p27 and will contribute to the understanding of the overall mechanism of p27 tumor suppression in a CDK-independent manner.

• Authors: Xun Che, Jinyi Liu, Haishan Huang, Xiaoyi Mi, Qing Xia, Jingxia Li, Dongyun Zhang, Qingdong Ke, Jimin Gao, Chuanshu Huang
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1833 Issue 9 Pg. 2083-91 (Sep 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23639288 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Arsenites
• Cdkn1b protein, mouse
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Teratogens
• Cyclin-Dependent Kinase Inhibitor p27
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Mitogen-Activated Protein Kinase 13
• Mitogen-Activated Protein Kinase 11
• arsenite

Topics

• Animals
• Arsenites (pharmacology)
• Cell Line
• Cyclic AMP Response Element-Binding Protein (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• Cyclooxygenase 2 (biosynthesis, genetics)
• Gene Expression Regulation, Enzymologic (drug effects, genetics)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 11 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 13 (genetics, metabolism)
• Phosphorylation (drug effects, genetics)
• Teratogens (pharmacology)
• Transcription, Genetic (drug effects, genetics)