Title: p27 suppresses cyclooxygenase-2 expression by inhibiting p38β and p38δ-mediated CREB phosphorylation upon arsenite exposure.
Authors: Che, Xun; Liu, Jinyi; Huang, Haishan; Mi, Xiaoyi; Xia, Qing; Li, Jingxia; Zhang, Dongyun; Ke, Qingdong; Gao, Jimin; Huang, Chuanshu
Published In Biochim Biophys Acta, (2013 Sep)
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.
PubMed ID: 23639288
MeSH Terms: Animals; Arsenites/pharmacology*; Cell Line; Cyclic AMP Response Element-Binding Protein/genetics; Cyclic AMP Response Element-Binding Protein/metabolism*; Cyclin-Dependent Kinase Inhibitor p27/genetics; Cyclin-Dependent Kinase Inhibitor p27/metabolism*; Cyclooxygenase 2/biosynthesis*; Cyclooxygenase 2/genetics; Gene Expression Regulation, Enzymologic/drug effects*; Gene Expression Regulation, Enzymologic/genetics; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 11/genetics; Mitogen-Activated Protein Kinase 11/metabolism*; Mitogen-Activated Protein Kinase 13/genetics; Mitogen-Activated Protein Kinase 13/metabolism*; Phosphorylation/drug effects; Phosphorylation/genetics; Teratogens/pharmacology*; Transcription, Genetic/drug effects; Transcription, Genetic/genetics