title: 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: Nelson Institute of Environmental Medicine, New York University, School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors: Xun
authors: X
authors: Che
authors: Jinyi
authors: J
authors: Liu
authors: Haishan
authors: H
authors: Huang
authors: Xiaoyi
authors: X
authors: Mi
authors: Qing
authors: Q
authors: Xia
authors: Jingxia
authors: J
authors: Li
authors: Dongyun
authors: D
authors: Zhang
authors: Qingdong
authors: Q
authors: Ke
authors: Jimin
authors: J
authors: Gao
authors: Chuanshu
authors: C
authors: Huang
mesh_terms: D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D013723:Teratogens / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D018053:Arsenites; C493961:Cdkn1b protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D013723:Teratogens; D050760:Cyclin-Dependent Kinase Inhibitor p27; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048292:Mitogen-Activated Protein Kinase 13; D048290:Mitogen-Activated Protein Kinase 11; C015001:arsenite
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