Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

Bile acids: regulation of synthesis.

https://jivaresearch.org/research/curcumin/Inflammation_and_cancer-_how_hot_is_the_link.pdf

Inflammation and cancer: How hot is the link?

Rel/NF-kappaB transcription factors are key regulators of immune, inflammatory and acute phase responses and are also implicated in the control of cell proliferation and apoptosis. Remarkable progress has been made in understanding the signal transduction pathways that lead to the activation of Rel/NF-kappaB factors and the consequent induction of gene expression. Evidence linking deregulated Rel/NF-kappaB activity to oncogenesis in mammalian systems has emerged in recent years, consistent with the acute oncogenicity of the viral oncoprotein v-Rel in animal models. Chromosomal amplification, overexpression and rearrangement of genes coding for Rel/NF-kappaB factors have been noted in many human hematopoietic and solid tumors. Persistent nuclear NF-kappaB activity was also described in several human cancer cell types, as a result of constitutive activation of upstream signaling kinases or mutations inactivating inhibitory IkappaB subunits. Studies point to a correlation between the activation of cellular gene expression by Rel/NF-kappaB factors and their participation in the malignant process. Experiments implicating NF-kappaB in the control of the apoptotic response also support a role in oncogenesis and in the resistance of tumor cells to chemotherapy. This review focuses on the status of the rel, nfkb and ikb genes and their activity in human tumors and their association with the onset or progression of malignancies.

Aberrant rel/nfkb genes and activity in human cancer.

The proteasome is an abundant multi-enzyme complex that provides the main pathway for degradation of intracellular proteins in eukaryotic cells. As such, it controls the levels of proteins that are important for cell-cycle progression and apoptosis in normal and malignant cells; for example, cyclins, caspases, BCL2 and nuclear factor of κB. A proteasome inhibitor — bortezomib — has been developed that has shown efficacy as an anticancer agent in the clinic. How can targeting such a universal, broadly active cellular component provide the selectivity and specificity that are required for cancer therapeutics?

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

The proteasome: a suitable antineoplastic target

NF- κ B transcription factor induces drug resistance through MDR1 expression in cancer cells

NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells

Radioactive assay for aryl hydrocarbon hydroxylase. Improved method and biological importance.

Microsomes were prepared from human livers obtained from renal donors of various ages and both sexes. Their drug-metabolizing capacity was measured and compared to that of rat liver microsomes. The following parameters were investigated: cytochrome P-450, cytochrome B5, NADPH-cytochrome c reductase, epoxide hydrolase, aryl hydrocarbon hydroxylase, benzphetamine N-demethylase, p-nitroanisole-O-demethylase, ethoxycoumarin-O-deethylase, steroid-16 alpha-hydroxylase. In addition, the metabolism of benzo(a)pyrene, progesterone, pregnenolone, testosterone, dehydroepiandrosterone and estradiol was studied in detail in vitro. The inhibitory effect of metyrapone and alpha-naphthoflavone on 7-ethoxycoumarin-O-deethylase was measured. The microsomal proteins of both species were separated by polyacrylamide gel electrophoresis in the presence of dodecyl sulfate. The following conclusions were drawn from the results obtained. Human liver microsomes can be stored under optimal conditions for the measurement of a large variety of enzymic activities. Human liver microsomes are able to metabolize the various xenobiotics used as substrates with a rate similar to that of female rat liver microsomes. No sex-linked difference in enzymic activity was observed in human microsomes. Significant differences in benzo(a)pyrene and steroid metabolism were registered when human and rat liver microsomes were compared. The monooxygenase activities, the sensitivity to in vitro alpha-naphthoflavone and metyrapone, the results of steroid metabolism, and slab gel electrophoresis are strong indications for multiplicity of human liver cytochrome P-450.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1432-1033.1981.tb05561.x

Cytochrome P-450 Monooxygenase Activities in Human and Rat Liver Microsomes

The establishement of the circadian rhythm of cholesterol 7α-hydroxylase activity requires protein and RNA synthesis. The spontaneous decrease of the enzymic activity, at the end of the night, allows us to evaluate a half-life time of about two hours. The half-life time goes up to about four hours when the enzymatic activity decay is measured following cycloheximide administration. This difference suggests that an active mechanism is involved in the control of the enzyme degradation. The daily variation of the enzyme activity is regulated via the hypothalamo-hypophysis-adrenal axis. At the cellular level glucocorticoids are the most likely responsible agent. The hepatic cholesterol 7α-hydroxylase variations always parallel the plasmatic corticosterone concentration fluctuations, the latter being by far the most important adrenocortical excretion product. These two rhythms are modified in a similar manner under different physio-pathological conditions, such as the inversion of lighting in the animal room or the inversion of feeding time. Of these two parameters, the moment of food intake is the most important and accounts for the synchronisation of the rhythm in the animals. The rhythm is retained after several days of starvation but its amplitude decreases and the individual variations among the animals increase significantly at each time point.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1975.tb02134.x

Rat‐Liver Cholesterol 7α‐Hydroxylase

Constitutive NF-κB activity varies widely among cancer cell lines. In this report, we studied the expression and the role of different IκB inhibitors in adenocarcinoma cell lines. High constitutive NF-κB activity and low IκB-α expression was found in a number of these cell lines. Moreover, some of these cells showed a high p100 expression, responsible for the cytoplasmic sequestration of most of p65 complexes. Treatment of these cells with TNF-α or other NF-κB activating agents induced only weakly nuclear NF-κB activity without significant p100 processing and led to a very weak transcription of NF-κB-dependent reporter gene. Induction of NF-κB activity can be restored by expression of the Tax protein or by treatment with antisense p100 oligonucleotides. In MCF7 A/Z cells stably transfected with a p100 expression vector, p65 complexes were sequestered in the cytoplasm by p100. These cells showed a reduced nuclear NF-κB induction and NF-κB-dependent gene transcription following TNF-α stimulation. As a consequence of a competition between IκB-α and p100, cells expressing high levels of p100 respond poorly to NF-κB activating stimuli as TNF-α.

Jacques Gielen

Papers

NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells

Radioactive assay for aryl hydrocarbon hydroxylase. Improved method and biological importance.

Cytochrome P-450 Monooxygenase Activities in Human and Rat Liver Microsomes

Rat‐Liver Cholesterol 7α‐Hydroxylase

Regulation of NF-kappaB activity by I kappaB-related proteins in adenocarcinoma cells.