ERK Oscillation-Dependent Gene Expression Patterns and Deregulation by Stress Response

详细信息    查看全文

• 作者：Katrina M. Waters ; Brian S. Cummings ; Harish Shankaran ; Natalie E. Scholpa ; Thomas J. Weber
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：September 15, 2014
• 年：2014
• 卷：27
• 期：9
• 页码：1496-1503
• 全文大小：406K
• ISSN：1520-5010

文摘

Studies were undertaken to determine whether extracellular signal regulated kinase (ERK) oscillations regulate a unique subset of genes in human keratinocytes and subsequently whether the p38 stress response inhibits ERK oscillations. A DNA microarray identified many genes that were unique to ERK oscillations, and network reconstruction predicted an important role for the mediator complex subunit 1 (MED1) node in mediating ERK oscillation-dependent gene expression. Increased ERK-dependent phosphorylation of MED1 was observed in oscillating cells compared to nonoscillating counterparts as validation. Treatment of keratinocytes with a p38 inhibitor (SB203580) increased ERK oscillation amplitudes and MED1 and phospho-MED1 protein levels. Bromate is a probable human carcinogen that activates p38. Bromate inhibited ERK oscillations in human keratinocytes and JB6 cells and induced an increase in phospho-p38 and a decrease in phospho-MED1 protein levels. Treatment of normal rat kidney cells and primary salivary gland epithelial cells with bromate decreased phospho-MED1 levels in a reversible fashion upon treatment with p38 inhibitors (SB202190; SB203580). Our results indicate that oscillatory behavior in the ERK pathway alters homeostatic gene regulation patterns and that the cellular response to perturbation may manifest differently in oscillating vs nonoscillating cells.