Histone H3 phosphorylation, immediate-early gene expression, and the nucleosomal response: a historical perspective¹This article is part of Special Issue entitled Asilomar Chromatin and has undergone the Journal’s usual peer review process.

Abstract

Histone H3 is modified at serines 10 and 28 in interphase cells following activation of the RAS-MAPK or p38-MAPK pathways by growth factors or stress. These modifications are involved in the regulation of immediate-early genes, including Jun and Fos, whose increased expression is a trademark of various cancers. This review outlines the series of discoveries that led to the characterization of these modifications, the kinase, MSK1/2, which is activated by both MAPK pathways and directs phosphorylation of H3, and the mechanistic function of these modifications in transcriptional activation. Research examining the effect of deregulated MSK1/2 in human disorders, namely cancer, is evaluated. Recently, a number of reports proposed novel, intervening pathways leading to enrichment of phosphorylated serine 10 and 28 and the activation of MSK1/2. These novel pathways predict an even more complicated signalling mechanism for cell growth, apoptosis, and the immune response, suggesting that MSK1/2 is intrinsically responsible for an even greater number of biological processes. This review proposes that MSK1/2 is an optimal target for cancer therapy, based on its fundamental role in transmitting external signals into varied responses involved in cancer development.

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

“…Consistent with this, in all breast cancer cell lines we observe a strong increase in Ser10 phosphorylation of histone H3 (Figure 5F), a histone modification associated with chromatin condensation in prophase [59–61], as well as immediate early gene transcription [62]. Neither a G2/M arrest nor a robust increase in Ser10 phosphorylation of histone H3 occurs in non-transformed MCF10A cells treat at the same concentrations of DY131.…”

“…p38 can directly phosphorylate H2AX in vitro [63] and is responsible for apoptosis-associated in vivo γH2AX induction either directly or through activation of downstream kinases such as mitogen-activated protein kinase activated kinase 2 (MAPKAPK2) [64, 65]. Similarly, p38 can phosphorylate H3 Ser10 directly in vitro [66], as can the p38 substrate mitogen- and stress-activated protein kinase 1 (MSK1) [62]. …”

ERK-Induced Activation of TCF Family of SRF Cofactors Initiates a Chromatin Modification Cascade Associated with Transcription

“…Thus, the five histone modifications can be placed in the order H3K9acS10ph, H4K16ac, H3K27ac, H3K9acK14ac, and H3K4me3 according to the magnitude of the TPA-induced change at each TSS. Several studies have implicated H3 phosphorylation as an early step in the response to ERK and SAPK activation (for review, see Healy et al., 2012), consistent with the notion that this ordering might reflect a temporal sequence (see below).…”

“…Our data suggest these modifications may generally occur at inducible genes. H3 phosphorylation is thought to promote chromatin de-compaction and to facilitate chromatin regulatory events (for review, see Healy et al., 2012). For example, targeting of the H3 kinase MSK directly to promoters can induce both H3 phosphorylation and gene transcription (Lau and Cheung, 2011), and recent studies have shown that H3S28 phosphorylation potentiates transcription on chromatin templates in vitro (Josefowicz et al., 2016).…”

“…Phosphorylation of H3 at serine 10 and 28, first seen to be associated with mitogen- and stress-induced gene activation (Clayton et al., 2000; for review, see Healy et al., 2012, Mahadevan et al., 1991, Soloaga et al., 2003, Zhong et al., 2001), accompanies gene activation induced by NFκB, HSF, progesterone receptor, and ectopic Gal4 expression (Anest et al., 2003, Labrador and Corces, 2003, Nowak and Corces, 2000, Vicent et al., 2006, Yamamoto et al., 2003). In different contexts, H3 phosphorylation has been associated with recruitment of regulatory cofactors, chromatin modifiers, and remodelers (Cheung et al., 2000, Drobic et al., 2010, Josefowicz et al., 2016, Lo et al., 2000, Zippo et al., 2009), and with displacement of repressors (Lau and Cheung, 2011, Sawicka et al., 2014).…”