title: Histone H3 phosphorylation, immediate-early gene expression, and the nucleosomal response: a historical perspective.
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.
authors.affiliation: MB Institute of Cell Biology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Healy
authors.forename: Protiti
authors.initials: P
authors.lastname: Khan
authors.forename: Shihua
authors.initials: S
authors.lastname: He
authors.forename: James R
authors.initials: JR
authors.lastname: Davie
mesh_terms: D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000235:genetics*; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy; D009707:Nucleosomes / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*
chemical_list: D006657:Histones; D009707:Nucleosomes; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1