Histone H3 phosphorylation, immediate-early gene expression, and the nucleosomal response: a historical perspective.

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.

Tropomyosin as a regulator of cancer cell transformation.

Tropomyosins (Tms) are among the most studied structural proteins of the actin cytoskeleton that are implicated in neoplastic-specific alterations in actin filament organization. Decreased expression of specific nonmuscle Tm isoforms is commonly associated with the transformed phenotype. These changes in Tm expression appear to contribute to the rearrangement of microfilament bundles and morphological alterations, increased cell motility and oncogenic signaling properties of transformed cells. Below we review aspects of Tm biology as it specifically relates to transformation and cancer including its expression in culture models of transformed cells and human tumors, mechanisms that regulate Tm expression and the role of Tm in oncogenic signaling.

Immediate early response genes and cell transformation.

Cancer has been described as not one disease, but several, each with unique characteristics, symptoms, prognostics and outcomes. Underlying this complexity is a differential expression of genes, leading to a motley of phenotypes which orchestrate the hallmarks of cancer. The idea of treating, suppressing or even preventing all forms of cancer with a single form of therapy seems untenable given the complexities of these gene expression profiles. However, recent advances in the study of immediate early genes, a family of genes that are rapidly and transiently upregulated following an external stimulus such as growth factors, hormones or stress, and their ubiquitous involvement in regulating oncogenomic responses may lend itself to new and unique therapies. At the very least, understanding and targeting immediate early gene expression and function remains an untapped area in cancer prevention research, and could very well provide new resources in cancer treatment and new perspectives in directed cancer suppression. In this review, we will discuss the critical role immediate early genes play in cancer progression, and provide specific examples of immediate early gene function and inhibition.

Mitogen- and stress-activated protein kinases 1 and 2 are required for maximal trefoil factor 1 induction.

Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2), activated downstream of the ERK- and p38-mitogen-activated protein kinase pathways are involved in cell survival, proliferation and differentiation. Following mitogenic or stress stimuli, they mediate the nucleosomal response, which includes phosphorylation of histone H3 at serine 10 (H3S10ph) coupled with transcriptional activation of immediate-early genes. While MSK1 and MSK2 are closely related, their relative roles may vary with cellular context and/or stimuli. However, our knowledge of MSK2 recruitment to immediate-early genes is limited, as research has primarily focused on MSK1. Here, we demonstrate that both MSK1 and MSK2, regulate the phorbol ester 12-O-tetradecanoylphorbol-13-acetate induced expression of the breast cancer marker gene, trefoil factor 1 (TFF1), by phosphorylating H3S10 at its 5' regulatory regions. The MSK-mediated phosphorylation of H3S10 promotes the recruitment of 14-3-3 isoforms and BRG1, the ATPase subunit of the BAF/PBAF remodeling complex, to the enhancer and upstream promoter elements of TFF1. The recruited chromatin remodeling activity leads to the RNA polymerase II carboxy-terminal domain phosphorylation at the TFF1 promoter, initiating TFF1 expression in MCF-7 breast cancer cells. Moreover, we show that MSK1 or MSK2 is recruited to TFF1 regulatory regions, but as components of different multiprotein complexes.

Current understanding and importance of histone phosphorylation in regulating chromatin biology.

The core histones H2A, H2B, H3 and H4, undergo various post-translational modifications, such as acetylation, methylation and phosphorylation. Core histone phosphorylation has roles in several biological responses, including transcription, mitosis, DNA repair and apoptosis. Histone phosphorylation may disrupt chromatin structure and/or provide a 'code' for the recruitment or occlusion of non-histone chromosomal proteins to chromatin. Among the better-characterized histone phosphorylation events are the phosphorylation of H3 at Ser10 and Ser 28, and the phosphorylation of the H2A variant H2A.X at Ser139. Much remains to be learned about the function of the many other core histone phosphorylation events in chromatin. This review provides an overview of the biological roles of core histone phosphorylation in mammalian cells.