Computational EST database analysis identifies a novel member of the neuropoietic cytokine family.

A novel member of the neuropoietic cytokine family has been cloned and the protein expressed and characterized. In an effort to identify novel secreted proteins, an algorithm incorporating neural network algorithms was applied to a large EST database. A full-length clone was identified that is 1710 bp in length and has a single open reading frame of 225 amino acids. This new cytokine is most homologous to cardiotrophin-1, having a similarity and an identity of 46 and 29%, respectively, and therefore we have named it cardiotrophin-like cytokine (CLC). Northern hybridization analysis identified a 1.4-kb messenger RNA that is highly expressed in spleen and peripheral leukocytes. Purified recombinant CLC induced the activation of NFkappaB and SRE reporter constructs in the TF-1, U937, and M1 cell lines. Furthermore, the signal transduction pathway for CLC was characterized in the neuroblastoma cell line SK-N-MC and found to involve tyrosine phosphorylation of gp130 and STAT-1.     

The emerging neuropoietic cytokine family: first CDF/LIF, CNTF and IL-6; next ONC, MGF, GCSF?

CDF/LIF is a polyfunctional cytokine that shares a remarkable overlap with ciliary neurotrophic factor in its actions on neurons, and with interleukin-6 in its actions on other tissues. Moreover, the receptors for this cytokine, as well as those for ciliary neurotrophic factor, share homology with the subunits of the interleukin-6 receptor. The predicted structural similarity of these proteins with oncostatin M, myelomonocytic growth factor and granulocyte colony-stimulating factor, as well as at least a partial overlap in biological activities, is now prompting further examination of their roles in neuronal gene expression.     

Evolutionary plasticity of IL-6 cytokine family

The IL-6 family of cytokines includes a variety of proteins that function not only within the immune system, but also in other organs, tissues, and types of cells, including neurons. The common evolutionary origin of the IL-6 family proteins determines similar mechanisms of reception and intracellular signaling, although their primary structures are highly variable, as well as their biological functions. We have demonstrated that the members of the IL-6 family have high evolutionary plasticity. This manifests in a high degree of population polymorphism for IL-6 family genes, as well as varying degrees of evolutionary conservation among members of the family. The degree of evolutionary conservation of IL-6 family proteins does not correlate with the mechanisms of interaction between these cytokines and their receptors.     

Hippo signaling and epithelial cell plasticity in mammalian liver development,homeostasis, injury and disease

A traditional view of cellular differentiation is unidirectional: progenitor cells adopt specific fates in response to environmental cues resulting in deployment of cell-specific gene expression programs and acquisition of unique differentiated cellular properties such as production of structural and functional proteins that define individual cell types. In both development and in tissue repair stem and progenitor cells are thought to both self-renew to maintain the pool of precursors and to expand to give rise to transient amplifying and differentiated cell types. Recently, however, it has become appreciated that differentiated cell types can be reprogrammed to adopt progenitor and stem cell properties. In the case of epithelial cells in the mammalian liver, hepatocytes and biliary epithelial cells there is a significant degree of plasticity between these lineages that has been implicated in mechanisms of tissue repair and in liver pathologies such as cancer. Recent studies have highlighted the role of Hippo signaling, an emerging growth control and tumor suppressor pathway, in regulating epithelial cell plasticity in the mammalian liver and in this review, the role of cellular plasticity and Hippo signaling in regulating normal and abnormal tissue responses in the mammalian liver will be discussed.     

Epidermal growth factor promotes a neural phenotype in thymic epithelial cells and enhances neuropoietic cytokine expression

Neural crest-derived cells populate the thymus, and their coexistence with epithelial cells is required for proper organ development and T cell education function. We show here that epidermal growth factor (EGF), a major epithelial cell growth-enhancing agent, has a morphogenetic action to promote the expression of a neuronal phenotype (e.g., neurofilament expression) in cultured thymic epithelial cells that are characterized by a cytokeratin-positive epithelial cell background. The proliferation of such neurodifferentiated cells is also enhanced by EGF. Furthermore, the growth factor enhances cells that express the genes encoding the preprotachykinin A-generated neuropeptides and bipotential neuropoietic and lymphopoietic cytokines ciliary neurotrophic factor and interleukin-6. These cytokines also enhance the neuronal phenotype of thymic epithelial cells. Therefore, EGF appears to be a composite autocrine/paracrine neuromodulator in thymic stroma. This suggests that EGF may regulate thymus-dependent immune functions by promoting neuronal gene expression in neural crest- derived cells.     

The p53 family in nervous system development and disease

The p53 family, consisting of the tumor suppressors p53, p63 and p73, play a vital role as regulators of survival and apoptosis in the developing, adult and injured nervous system. These proteins function as key survival and apoptosis checkpoints in neurons, acting as either rheostats or sensors responsible for integrating multiple pro-apoptotic and survival cues. A dramatic example of this checkpoint function is observed in developing sympathetic neurons, where a pro-survival and truncated form of p73 antagonizes the apoptotic functions of p53 and p63. Thus the levels and activities of the different p53 family members may ultimately determine whether neurons either live or die during nervous system development and disease.     

Variation, plasticity and modularity in anuran development

Although anuran development is generally thought to be relatively conservative, a great deal of variation is evident when different species are compared. This report summarizes the results of comparative analyses of different aspects of anuran development. These include differences in sequence and timing of developmental events, the effects of genome size, and the effects of different life history strategies on anuran embryogenesis. The results show that anuran development is plastic at the evolutionary level, and many changes can occur in the developmental processes of anurans throughout their evolution. Changes are apparently rapid, and are as common as cladogenic events. This evolutionary plasticity can be attributed to the modular nature of anuran development. Different modules can shift relative to one another in time or in space, creating variations in the observed developmental patterns. However, shifts in modules can occur even without having a significant effect on the ultimate outcome of the process. I discuss the implications of the modular nature of development on the evolution of anuran development, and of the group in general.     

The IL-2 cytokine family in cancer immunotherapy

The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.     

The STAT family of proteins in cytokine signaling

It has now been well established that the STAT family of proteins play important roles in cytokine-mediated specific gene activation. Although significant progress has been made toward the understanding of the structure and function of STATs as well as the regulation of STAT signaling pathways, many important questions remain to be answered. STAT PTPase(s) and STAT serine kinase(s) which play important roles in regulating STAT activity have not been identified. In addition, the molecular mechanisms of the negative regulation of STAT signaling by recently discovered protein inhibitors and the crosstalk between STAT and other signal transduction pathways have not been understood. The JAK/STAT field remains to be challenging and exciting.     

The pur protein family: Genetic and structural features in development and disease

The Pur proteins are an ancient family of sequence‐specific single‐stranded nucleic acid‐binding proteins. They bind a G‐rich element in either single‐ or double‐stranded nucleic acids and are capable of displacing the complementary C‐rich strand. Recently several reports have described Pur family member knockouts, mutations, and disease aberrations. Together with a recent crystal structure of Purα, these data reveal conserved structural features of these proteins that have been adapted to serve functions unique to higher eukaryotes. In humans Pur proteins are critical for myeloid cell development, muscle development, and brain development, including trafficking of mRNA to neuronal dendrites. Pur family members have been implicated in diseases as diverse as cancer, premature aging, and fragile‐X mental retardation syndrome. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.     

Tet family proteins and 5-hydroxymethylcytosine in development and disease

Over the past few decades, DNA methylation at the 5-position of cytosine (5-methylcytosine, 5mC) has emerged as an important epigenetic modification that plays essential roles in development, aging and disease. However, the mechanisms controlling 5mC dynamics remain elusive. Recent studies have shown that ten-eleven translocation (Tet) proteins can catalyze 5mC oxidation and generate 5mC derivatives, including 5-hydroxymethylcytosine (5hmC). The exciting discovery of these novel 5mC derivatives has begun to shed light on the dynamic nature of 5mC, and emerging evidence has shown that Tet family proteins and 5hmC are involved in normal development as well as in many diseases. In this Primer we provide an overview of the role of Tet family proteins and 5hmC in development and cancer.