Activators and Target Genes of Rel/NF-кB Transcription Factors: From Bench to Bedside

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.

http://dipbsf.uninsubria.it/monti/BFPN%202009/HDACi2.pdf

Anticancer activities of histone deacetylase inhibitors.

The choice between life and death is one of the major events in regulation of the immune system. T cells that specifically recognize viral or bacterial antigens are selected to survive and proliferate in response to infection, whereas those that are self-reactive are eliminated via apoptosis. Even the survival of alloreactive T cells requires their proper costimulation and, when infection subsides, the activated T cells are eliminated. A major regulator of such life or death decisions is the transcription factor NF-κB. However, NF-κB cannot function alone. A variety of mechanisms exist to modulate its activity and thereby affect the ultimate outcome of a cell's fate.

/pdf/nf-kb-at-the-crossroads-of-life-and-death-1skki097u9.pdf

NF-κB at the crossroads of life and death

A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed. Cell Death and Differentiation (2003) 10, 45–65. doi:10.1038/ sj.cdd.4401189

/pdf/tumor-necrosis-factor-signaling-4agufl4zu9.pdf

Tumor necrosis factor signaling.

http://cinjweb.umdnj.edu/sites/molmdweb/documents/Gretenetal.pdf

IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.

The transcription factors of the Rel/NF-kappaB family are key regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the Rel/NF-kappaB oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-kappaB control. Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-kappaB raised the issue of whether NF-kappaB is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate that NF-kappaB differentially regulates the expression of particular Bcl-2-related death inhibitors and that it directly activates the expression of Bcl-x(L). While Bcl-x(L) was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-kappaB factors also upregulated bcl-x gene expression and this effect was antagonized by an inhibitor of NF-kappaB activity. The expression of bcl-x suppressed apoptosis in the presence or absence of NF-kappaB activity. Functional analysis of the bcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-kappaB directly regulates the expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-x(L) and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with aberrant Rel/NF-kappaB activity.

The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L).

I kappa B alpha is a dual regulator of Rel/NF-kappa B transcription factors. I kappa B alpha retains inactive NF-kappa B dimers in the cytoplasm, and inhibits their DNA-binding and transcriptional activities in the nucleus. Our previous studies identified discrete functional domains in I kappa B alpha responsible for the cytoplasmic and nuclear regulation of c-Rel. Determinants necessary for regulating c-Rel in the nucleus mapped to the central ankyrin domain of I kappa B alpha and a few negatively-charged amino acids that follow in the C-terminal PEST region. In contrast, sequences involved in the cytoplasmic regulation of c-Rel reside in the N-terminal and central ankyrin domains of I kappa B alpha. Here, we present a refined mapping of the N-terminal determinants of I kappa B alpha necessary for the cytoplasmic regulation of c-Rel homodimers. We demonstrate that amino acids 48 - 58 in p40/I kappa B alpha are essential to block the nuclear localization of c-Rel dimers. These data define a region of I kappa B alpha that may be required for optimal masking of the c-Rel NLS, or for the nuclear export of c-Rel/I kappa B alpha complexes. These findings highlight a novel function for the N-terminus of I kappa B alpha in the control of the subcellular localization of Rel/NF-kappa B dimers. Given the implication of deregulated NF-kappa B activity in hematopoietic and solid tumors, our findings predict that certain alterations in this domain of I kappa B alpha may have severe biological repercussions.

N-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel

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The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L).

N-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel