Nucleosomal response, immediate-early gene expression and cell transformation

The induced nucleosomal response mediated by a stimulated RAS–MAPK–MSK pathway or through inhibition of protein phosphatases is central in gene expression programs in normal and disease states. The induced H3S10ph or H3S28ph is located in nucleosomes associated with the promoter of responsive genes. MSK mediated H3 phosphorylation is one of the steps towards chromatin remodeling at these promoters, leading to the onset of transcription. As a downstream target of MAPK signaling pathways, H3 phosphorylation is a response to a vast array of extracellular stimuli including growth factors, stressors such as UV light, alcohol and neurotransmitters. Consequently, H3 phosphorylation is a crucial intermediate step conveying a signal received by a cell-surface receptor to specific promoters thus triggering chromatin remodeling and transcriptional reprogramming. The outcome of H3 phosphorylation varies with the stimuli and cellular contexts. In postmitotic neurons, H3 phosphorylation plays a role in award-related and behavioral learning, long-term memory processes and regulation of the circadian clock. In tumorigenic and cancer cell lines, persistent activation of signaling pathways resulting in elevated steady state levels of H3 phosphorylation correlates with abnormal gene expression and uncontrolled growth or metastasis. Most importantly, MSK activity is required for cell transformation initiated by a variety of oncogenes such as Ras and v-Src. MSK and the nucleosomal response are involved in the inflammatory response (Beck et al., 2009). As a deregulated inflammatory response can lead to cancer (Aggarwal and Gehlot, 2009), MSK is a potential therapeutic target for cancer prevention and treatment.