title: Alternariol induces DNA polymerase β expression through the PKA-CREB             signaling pathway.
abstract: Alternariol (AOH) is a mycotoxin of Alternaria alternata and can cause DNA damage and gene mutations. Low-dose and long-term treatment with AOH has been linked with incidence of esophageal carcinoma. DNA polymerase β (polβ) is a key enzyme in DNA base excision repair (BER). When it is overexpressed or mutated in cells, DNA polβ can cause genetic instability. Elevated DNA polβ has also been reported in several human cancers. Here, we report that AOH at 2, 10, 20 µM induces DNA polβ expression. In the process, protein kinase A (PKA) catalytic subunit activation, nuclear translocation and cAMP response element binding protein (CREB) phosphorylation are involved. AOH also increased CREB binding to the cAMP response element (CRE) consensus motif, which is present in the DNA polβ gene promoter. The PKA inhibitor H89 was able to block AOH-induced PKA-CREB activation, CREB DNA binding activity and decrease DNA polβ expression. Our results suggest that AOH can upregulate DNA polβ expression through the PKA-CREB signal transduction pathway.
authors.affiliation: Department of Pathophysiology, School of Basic Medical Sciences,                     Zhengzhou University, Zhengzhou 450001, P.R. China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Zhao
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Junfen
authors.initials: J
authors.lastname: Ma
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yang
authors.forename: Ge
authors.initials: G
authors.lastname: Jin
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhao
authors.forename: Mingyao
authors.initials: M
authors.lastname: Zhao
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002273:Carcinogens; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007546:Isoquinolines; D007783:Lactones; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases; D019951:DNA Polymerase beta; C005197:alternariol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide