Bruck, N. et al. A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARα to target promoters. EMBO J. 28, 34-47

Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U596, CNRS UMR7104, Université Louis Pasteur de Strasbourg, CU de Strasbourg, France.
The EMBO Journal (Impact Factor: 10.43). 01/2009; 28(1):34-47. DOI: 10.1038/emboj.2008.256
Source: PubMed


The nuclear retinoic acid (RA) receptor alpha (RARalpha) is a transcriptional transregulator that controls the expression of specific gene subsets through binding at response elements and dynamic interactions with coregulators, which are coordinated by the ligand. Here, we highlighted a novel paradigm in which the transcription of RARalpha target genes is controlled by phosphorylation cascades initiated by the rapid RA activation of the p38MAPK/MSK1 pathway. We demonstrate that MSK1 phosphorylates RARalpha at S369 located in the ligand-binding domain, allowing the binding of TFIIH and thereby phosphorylation of the N-terminal domain at S77 by cdk7/cyclin H. MSK1 also phosphorylates histone H3 at S10. Finally, the phosphorylation cascade initiated by MSK1 controls the recruitment of RARalpha/TFIIH complexes to response elements and subsequently RARalpha target gene activation. Cancer cells characterized by a deregulated p38MAPK/MSK1 pathway, do not respond to RA, outlining the essential contribution of the RA-triggered phosphorylation cascade in RA signalling.

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    • "ERKs (ERK1–2) contribute to the growth of breast cancer cells and are activated by many stimuli. Like p38-MAPKs, ERKs phosphorylate MSK, which controls the activity of RARs [90]. ERKs can also phosphorylate Signal Transducer and Activator of Transcription 1/3 (STAT1/3), ERa, c-JUN and c-FOS which are active in mammary tumor cells and are regulated by retinoids [26,96–98]. "
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    ABSTRACT: All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of pre-clinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross-talk with relevant intra-cellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer.
    Cancer Treatment Reviews 01/2014; 40(6). DOI:10.1016/j.ctrv.2014.01.001 · 7.59 Impact Factor
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    • "ERK1/2 MAPK pathways are activated in neuronal cells and embryonic stem cells by RA (Bost et al. 2002; Masi a et al. 2007), while in other cells types p38MAPK is activated by RA (Alsayed et al. 2001; Piskunov and Rochette-Egly 2012). This latter pathway can be upstream of activation of MSK1 (Bruck et al. 2009) and provides one mechanism by which a rapid action by RA to promote protein phosphorylation then feeds back to RARs more traditional role of control of transcription. These nongenomic and genomic mechanisms intersect as a result of MSK1′s phosphorylation of RARa, promoting its capacity to induce gene transcription. "
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    ABSTRACT: The retinoids are a family of compounds that in nature are derived from vitamin A or pro-vitamin A carotenoids. An essential part of the diet for mammals, vitamin A has long been known to be essential for many organ systems in the adult. More recently, however, they have been shown to be necessary for function of the brain and new discoveries point to a central role in processes ranging from neuroplasticity to neurogenesis. Acting in several regions of the central nervous system including the eye, hippocampus and hypothalamus, one common factor in its action is control of biological rhythms. This review summarizes the role of vitamin A in the brain; its action through the metabolite retinoic acid via specific nuclear receptors, and the regulation of its concentration through controlled synthesis and catabolism. The action of retinoic acid to regulate several rhythms in the brain and body, from circadian to seasonal, is then discussed to finish with the importance of retinoic acid in the regular pattern of sleep. We review the role of vitamin A and retinoic acid (RA) as mediators of rhythm in the brain. In the suprachiasmatic nucleus and hippocampus they control expression of circadian clock genes while in the cortex retinoic acid is required for delta oscillations of sleep. Retinoic acid is also central to a second rhythm that keeps pace with the seasons, regulating function in the hypothalamus and pineal gland.
    Journal of Neurochemistry 11/2013; 129(3). DOI:10.1111/jnc.12620 · 4.28 Impact Factor
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    • "RA- or cAMP-initiated phosphorylation of the RARα moiety of the PML-RARα protein occurs at RARα Ser369. This phosphorylation can be exerted by MSK1 and allows cyclin-dependent kinase 7 (CDK7) to phosphorylate RARα at Ser77 (Gaillard et al., 2006; Bruck et al., 2009). Mutation of the Ser369 phosphorylation site in PML-RARα yields a protein with decreased sensitivity to RA-triggered degradation which results in resistance to RA (Nasr et al., 2008). "
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    ABSTRACT: Post-translational modifications (PTMs) regulate multiple biological functions of the promyelocytic leukemia (PML) protein and also the fission, disassembly, and rebuilding of PML nuclear bodies (PML-NBs) during the cell cycle. Pathway-specific PML modification patterns ensure proper signal output from PML-NBs that suit the specific functional requirements. Here we comprehensively review the signaling pathways and enzymes that modify PML and also the oncogenic PML-RARα fusion protein. Many PTMs occur in a hierarchical and timely organized fashion. Phosphorylation or acetylation constitutes typical starting points for many PML modifying events, while degradative ubiquitination is an irreversible end point of the modification cascade. As this hierarchical organization of PTMs frequently turns phosphorylation events as primordial events, kinases or phosphatases regulating PML phosphorylation may be interesting drug targets to manipulate the downstream modifications and thus the stability and function of PML or PML-RARα.
    Frontiers in Oncology 12/2012; 2:204. DOI:10.3389/fonc.2012.00204
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