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Review NF-kappaB regulation: the nuclear response. 2009
Mankan AK, Lawless MW, Gray SG, Kelleher D, McManus R. · Department of Clinical Medicine and Institute of Molecular Medicine, Trinity College, Dublin, Ireland. · J Cell Mol Med. · Pubmed #19438970 No free full text.
Abstract: Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that tightly regulates the expression of a large cohort of genes. As a key component of the cellular machinery NF-kappaB is involved in a wide range of biological processes including innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. Appropriate regulation of NF-kappaB is critical for the proper function and survival of the cell. Aberrant NF-kappaB activity has now been implicated in the pathogenesis of several diseases ranging from inflammatory bowel disease to autoimmune conditions such as rheumatoid arthritis. Systems governing NF-kappaB activity are complex and there is an increased understanding of the importance of nuclear events in regulating NF-kappaB's activities as a transcription factor. A number of novel nuclear regulators of NF-kappaB such as IkappaB-zeta and PDZ and LIM domain 2 (PDLIM2) have now been identified, adding another layer to the mechanics of NF-kappaB regulation. Further insight into the functions of these molecules raises the prospect for better understanding and rational design of therapeutics for several important diseases.
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Review Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. free! 2006
Gray SG, Dangond F. · Department of Clinical Medicine, Institute of Molecular Medicine, Trinity Sciences Health Centre, St James's Hospital, Dublin, Ireland. · Epigenetics. · Pubmed #17998807 links to free full text
Abstract: Major recent advances in the field of chromatin remodeling have dramatically changed our understanding of the ways in which genes are regulated. Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are increasingly being implicated as direct or indirect components in the regulation of expression of neuronal, immune and other tissue specific genes. HDACs and HATs have been shown to play important roles in cell growth, cell cycle control, development, differentiation and survival. Mutations in genes that encode HDAC-binding proteins cause neurological disorders, such as MeCP2 mutations in Rett's syndrome. Mutations of CBP, a gene with HAT function, cause the mental retardation-associated Rubinstein-Taybi syndrome. Recently, HDAC inhibitors have been found to ameliorate progression of the spinal muscular atrophy (SMA) motor neuron disease and the Huntington disease mouse models. The neuroprotective role of HDAC inhibitors seems to extend to other diseases that share mechanisms of oxidative stress, inflammation and neuronal cell apoptosis. HDAC inhibitors also have widespread modulatory effects on gene expression within the immune system and have been used successfully in the lupus and rheumatoid arthritis autoimmune disease models. Recently, we demonstrated the efficacy of the HDAC inhibitor Trichostatin A in ameliorating disease in the multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In this review we describe the current literature surrounding these inhibitors and propose a rationale for harnessing both their neuroprotective and anti-inflammatory effects to treat MS, an autoimmune, demyelinating and degenerative disease of the human central nervous system (CNS).
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