Thomas D. Gilmore

Control of apoptosis by Rel/NF-κB transcription factors

Apoptosis is a physiological process critical for organ development, tissue homeostasis, and elimination of defective or potentially dangerous cells in complex organisms. Apoptosis can be initiated by a wide variety of stimuli, which activate a cell suicide program that is constitutively present in most vertebrate cells. In diverse cell types, Rel/NF-κB transcription factors have been shown to have a role in regulating the apoptotic program, either as essential for the induction of apoptosis or, perhaps more commonly, as blockers of apoptosis. Whether Rel/NF-κB promotes or inhibits apoptosis appears to depend on the specific cell type and the type of inducer. An understanding of the role of Rel/NF-κB transcription factors in controlling apoptosis may lead to the development of therapeutics for a wide variety of human diseases, including neurodegenerative and immune diseases, and cancer.

Good cop, bad cop: the different faces of NF-κB

Complexes formed from the nuclear factor κB (NF-κB) family of transcription factors are ubiquitously expressed and are induced by a diverse array of stimuli. This results in their becoming activated in a wide variety of different settings. While the functions of NF-κB in many of these contexts have been the subject of intense research and are now well established, it is also clear that there is great diversity in the effects and consequences of NF-κB activation. NF-κB subunits do not necessarily regulate the same genes, in an identical manner, in all of the different circumstances in which they are induced. This review will discuss the different functions of NF-κB, the pathways that modulate NF-κB subunit activity and, in contrast to its more commonly thought of role as a promoter of cancer cell growth and survival, the ability of NF-κB, under some circumstances, to behave as a tumor suppressor.

Transcription factor cross-talk: the estrogen receptor and NF-κB

The NF-κB family of transcription factors regulates many genes that are essential primarily for the development, maintenance and function of the innate and adaptive immune systems. Thus, aberrant activity of the nuclear factor NF-κB has a role in many pathological conditions with inflammatory and autoimmune components. Estrogen receptors (ERs) are transcription factors that mediate the biological responses to the sex hormone estrogen and are essential for reproduction and for functions of the cardiovascular, skeletal and nervous systems. Recent studies have demonstrated molecular cross-talk between these families of transcription factors in which the ER mediates inhibition of NF-κB activity at several levels. Such cross-talk between these important regulators of the endocrine and immune systems might be exploited for the treatment of cancer and inflammatory and autoimmune diseases.

Diverse agents act at multiple levels to inhibit the Rel/NF-κB signal transduction pathway

Rel/NF-κB transcription factors regulate several important physiological processes, including developmental processes, inflammation and immune responses, cell growth, cancer, apoptosis, and the expression of certain viral genes. Therefore, they have also been sought-after molecular targets for pharmacological intervention. As details of the Rel/NF-κB signal transduction pathway are revealed, it is clear that modulators of this pathway can act at several levels. Inhibitors of the Rel/NF-κB pathway include a variety of natural and designed molecules, including anti-oxidants, proteasome inhibitors, peptides, small molecules, and dominant-negative or constitutively active polypeptides in the pathway. Several of these molecules act as general inhibitors of Rel/NF-κB induction, whereas others inhibit specific pathways of induction. Inhibitors of Rel/NF-κB are likely to gain stature as treatments for certain cancers and neurodegenerative and inflammatory diseases.

Transformation by Rous sarcoma virus: A cellular substrate for transformation-specific protein phosphorylation contains phosphotyrosine

Transformation of chicken embryo fibroblasts by Rous sarcoma virus (RSV) is caused by a single viral gene, src, which encodes a phosphoprotein, pp60src, with the enzymatic activity of a protein kinase. The relative abundance of a 36,000 molecular weight (36K) phosphorylated polypeptide which can be detected by two-dimensional electrophoresis of 32P-labeled phosphoproteins is greatly increased in RSV-transformed fibroblasts. We have reported previously that phosphorylation of the 36K polypeptide is an early event in the process of transformation and that protein synthesis is not required for its appearance. Here we identify a nonphosphorylated 36K polypeptide, present in both uninfected and transformed cells, which is homologous to the 36K phosphoprotein as judged by limited proteolysis and by tryptic peptide mapping. We conclude that the 36K phosphoprotein is generated by phosphorylation of this 36K polypeptide. It has recently been shown that pp60src phosphorylates tyrosine residues in vitro: phosphotyrosine and also phosphoserine are present in the 36K phosphoprotein isolated from RSV-transformed cells. On the basis of these results we propose that the 36K polypeptide present in chicken fibroblasts is a substrate for the protein kinase activity of pp60src. Phosphorylation of this polypeptide may be important in cellular transformation by Rous sarcoma virus.

The IκB proteins: members of a multifunctional family

The I kappa B proteins bind to Rel/NF-kappa B transcription factors and modulate their activities. Although originally described only as cytoplasmic inhibitors of Rel/NF-kappa B transcription complexes, it is now clear that I kappa B proteins also have other functions.

Zyxin and paxillin proteins: focal adhesion plaque LIM domain proteins go nuclear

Zyxin and paxillin are the prototypes of two related subfamilies of LIM domain proteins that are localized primarily at focal adhesion plaques. However, recent work has shown that zyxin/paxillin family proteins also shuttle through the nucleus. These proteins may enter the nucleus by association with other proteins, but are exported from the nucleus by means of intrinsic leucine-rich nuclear export sequences. Zyxin/paxillin proteins may regulate gene transcription by interaction with transcription factors. In some cases, misregulation of nuclear functions of zyxin/paxillin proteins appear to be associated with pathogenic effects.

The c-Rel transcription factor and B-cell proliferation: a deal with the devil

Activation of the Rel/NF-κB signal transduction pathway has been associated with a variety of animal and human malignancies. However, among the Rel/NF-κB family members, only c-Rel has been consistently shown to be able to malignantly transform cells in culture. In addition, c-rel has been activated by a retroviral promoter insertion in an avian B-cell lymphoma, and amplifications of REL (human c-rel) are frequently seen in Hodgkins lymphomas and diffuse large B-cell lymphomas, and in some follicular and mediastinal B-cell lymphomas. Phenotypic analysis of c-rel knockout mice demonstrates that c-Rel has a normal role in B-cell proliferation and survival; moreover, c-Rel nuclear activity is required for B-cell development. Few mammalian model systems are available to study the role of c-Rel in oncogenesis, and it is still not clear what features of c-Rel endow it with its unique oncogenic activity among the Rel/NF-κB family. In any event, REL may provide an appropriate therapeutic target for certain human lymphoid cell malignancies.

NF-κB: where did it come from and why?

Summary:  The vast majority of research on nuclear factor κB (NF‐κB) signaling in the past 25 years has focused on its roles in normal and disease‐related processes in vertebrates, especially mice and humans. Recent genome and transcriptome sequencing efforts have shown that homologs of NF‐κB transcription factors, inhibitor of NF‐κB (IκB) proteins, and IκB kinases are present in a variety of invertebrates, including several in phyla simpler than Arthropoda, the phylum containing insects such Drosophila. Moreover, many invertebrates also contain genes encoding homologs of upstream signaling proteins in the Toll‐like receptor signaling pathway, which is well‐known for its downstream activation of NF‐κB for innate immunity. This review describes what we now know or can infer and speculate about the evolution of the core elements of NF‐κB signaling as well as the biological processes controlled by NF‐κB in invertebrates. Further research on NF‐κB in invertebrates is likely to uncover information about the evolutionary origins of this key human signaling pathway and may have relevance to our management of the responses of ecologically and economically important organisms to environmental and adaptive pressures.

Different localization of the product of the v-rel oncogene in chicken fibroblasts and spleen cells correlates with transformation by REV-T

Reticuloendotheliosis virus strain T (REV-T) is a highly oncogenic avian retrovirus that transforms early lymphoid cells in vivo and in vitro, but REV-T does not transform chicken embryo fibroblasts (CEF). Using antisera to p59v-rel, the v-rel oncogene product of REV-T, we show that p59v-rel is expressed at equal levels and is a phosphoprotein in REV-T infected spleen cells and CEF. Biochemical fractionation and immunofluorescence of REV-T infected nontransformed CEF show that p59v-rel is loosely associated with the nucleus. However, in REV-T transformed spleen cells p59v-rel is primarily a cytoplasmic protein. MSB-1 cells, a Mareks disease virus transformed T cell leukemic line, and E26 virus transformed myeloid cells show nuclear staining of p59v-rel when they are infected by REV-T. Our results indicate that there is a correlation between a cytoplasmic localization of p59v-rel and transformation by REV-T, and they suggest that p59v-rel cannot transform cells in which it assumes solely a nuclear location.