ERK phosphorylation of MED14 in promoter complexes during mitogen-induced gene activation by Elk-1

作者：Galbraith, Matthew D.; Saxton, Janice; Li, Li; Shelton, Samuel J.; Zhang, Hongmei; Espinosa, Joaquin M.; Shaw, Peter E.^*

来源：Nucleic Acids Research, 2013, 41(22): 10241-10253.

DOI：10.1093/nar/gkt837

• MAP KINASE
• TRANSCRIPTION FACTOR
• POSITIVE REGULATOR
• CROSS-TALK
• MEDIATOR
• COACTIVATOR
• MED23
• CDK8
• CELL
• RECRUITMENT

The ETS domain transcription factor Elk-1 stimulates expression of immediate early genes (IEGs) in response to mitogens. These events require phosphorylation of Elk-1 by extracellular signal-regulated kinase (ERK) and phosphorylation-dependent interaction of Elk-1 with co-activators, including histone acetyltransferases and the Mediator complex. Elk-1 also recruits ERK to the promoters of its target genes, suggesting that ERK phosphorylates additional substrates in transcription complexes at mitogen-responsive promoters. Here we report that MED14, a core subunit of the Mediator, is a bona fide ERK substrate and identify serine 986 (S986) within a serine-proline rich region of MED14 as the major ERK phosphorylation site. Mitogens induced phosphorylation of MED14 on S986 at IEG promoters; RNAi knockdown of MED14 reduced CDK8 and RNA polymerase II (RNAPII) recruitment, RNAPII C-terminal domain phosphorylation and impaired activation of IEG transcription. A single alanine substitution at S986 reduced activation of an E26 (ETS)-responsive reporter by oncogenic Ras and mitogen-induced, Elk-1-dependent transcription, whereas activities of other transcriptional activators were unaffected. We also demonstrate that Elk-1 can associate with MED14 independently of MED23, which may facilitate phosphorylation of MED14 by ERK to impart a positive and selective impact on mitogen-responsive gene expression.

• 出版日期2013-12
• 单位宁夏医科大学