The Kinases MSK1 and MSK2 Are Required for Epidermal Growth Factor-induced, but Not Tumor Necrosis Factor-induced, Histone H3 Ser10 Phosphorylation

Elizabeth A Duncan,Vasiliki Anest,Patricia Cogswell,Albert S Baldwin

doi:10.1074/jbc.m513333200

Abstract

Phosphorylation of histone H3 protein at serine 10 is an important step in chromatin remodeling during transcriptional transactivation. IkappaB kinase-alpha (IKK-alpha) and Mitogen- and Stress-activated protein Kinases 1 and 2 (MSK1/2) have been shown to play key roles in the transcriptional regulation of immediate early genes such as c-fos. Interestingly, IKK-alpha and MSK1/2 have also been implicated as histone H3-Ser10 kinases. In this work, we have shown that MSK1/2 are required for epidermal growth factor (EGF)-induced, but not tumor necrosis factor-induced, histone H3-Ser10 phosphorylation, both globally and at specific promoters. Consistent with this, MSK1/2 are required for optimal immediate early c-fos transcription in response to EGF potentially through control of both H3-Ser10 and promoter-associated cAMP-response element-binding protein phosphorylation. Furthermore, MSK1/2 control EGF-induced IkappaB alpha promoter H3-Ser10 phosphorylation in the absence of elevated transcription. These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression.

Highlights

Immediate early genes are characterized by rapid induction of transcription in response to a variety of stimuli including mitogens, stress, and cytokines [2,3,4]
We sought to determine whether MSK1 and MSK2 were required for transcriptional activation of c-fos in response to epidermal growth factor (EGF)
The data indicate that MSK1 and MSK2 are important for the efficient induction of c-fos gene expression in response to mitogenic treatment

Summary

Introduction

Immediate early genes are characterized by rapid induction of transcription in response to a variety of stimuli including mitogens, stress, and cytokines [2,3,4]. Because changes in gene-specific mRNA levels are regulated by several mechanisms, including transcriptional activation and mRNA degradation, a chromatin immunoprecipitation assay was used to assess the level of RNA polymerase II associated with the c-fos promoter in response to EGF stimulation.

Results

Conclusion