Progress in growth factor research最新文献

The etiology of Parkinson's disease, one of the most frequent neurodegenerative disorders in human, is unknown. New hopes concerning satisfactory therapies include transplants of autologous adrenal medullary chromaffin tissue, fetal mesencephalic dopaminergic neurons, and local application of growth factors with a neurotrophic capacity. A large body of evidence supports the notion that neurons require trophic support not only during a limited period of ontogenesis, but during their whole lifespan. Relevant molecules promote survival, transmitter synthesis and other differentiated properties, and become crucially important when a neuron is metabolically or toxically impaired. Several molecules, most of which occur in the striatum and the substantia nigra, have been identified that protect lesioned dopaminergic nigrostriatal neurons in culture or in animal models of Parkinson's disease. These include members of the neurotrophin, fibroblast growth factor, and insulin-like growth factor families as well as epidermal growth factor/transforming growth factor alpha, interleukins and ciliary neurotrophic factor. Whether their effects are merely pharmacological, or reflect a physiological role in the nigrostriatal system, is unclear as yet. This article reviews experiments that document the trophic effects of these factors on dopaminergic neurons and discusses their possible physiological and therapeutic relevance.

FGF6 is structurally very similar to the other members of the FGF gene family, and particularly to the FGF4 gene, which was instrumental in its isolation. Its longest open reading frame encodes a 208 amino acid residues long protein, both in man and in the mouse. It is expressed as a 4.8 kb transcript in skeletal muscle. In developing muscle, expression starts at the myotomal stage and culminates in differentiated fetal muscle masses. In culture, FGF6 protein is mitogenic and has a transforming capacity for fibroblasts. It represses the terminal differentiation of myoblasts. Action of FGF6 could be mediated by the FGFR4 receptor, which binds FGF6 and whose gene is also expressed in developing skeletal muscle.

Production of nitric oxide (NO) can be stimulated by inflammatory cytokines and bacterial lipopolysaccharide (LPS) in mammalian cells via an inducible nitric oxide synthase (iNOS). Conversely, the transforming growth factor-βs (TGF-βs) suppress NO production by reducing iNOS expression. Production of NO leads to disparate consequences, some beneficial and some damaging to the host, depending on the cell and context in which iNOS is induced. The TGF-βs counter these NO-mediated processes in macrophages, cardiac myocytes, smooth muscle cells, bone marrow cells, and retinal pigment epithelial cells. Autocrine or paracrine production of TGF-β may thus serve as a physiological counterbalance for iNOS expression, a mechanism which may be subverted by pathogens and tumors for their own survival. A greater understanding of the mechanisms and consequences of NO and TGF-β production may lead to effective therapeutic strategies in various diseases.

Neurotrophins comprise a family of basic homodimeric proteins. The isolation of the first two neurotrophins, nerve growth factor and brain-derived neurotrophic factor, was based on the ability of these proteins to promote the survival of embryonic neurons. However, the identification of additional neurotrophins by homology screening together with recent work on these proteins has shown that neurotrophins do more than just regulate neuronal survival. Neurotrophins influence the proliferation and differentiation of neuron progenitor cells and regulate the expression of several differentiated traits of neurons throughout life. Moreover, the influence of neurotrophins on survival is more complex than originally thought; some neurons switch their survival requirements from one set of neurotrophins to another during development and several neurotrophins may be involved in regulating the survival of a population of neurons at any one time. Most of what is known of the developmental physiology of neurotrophins has come from studying neurons of the peripheral nervous system. Quite apart from the accessibility of these neurons and their progenitor cell populations, investigation of the actions of neurotrophins on several well-characterised populations of sensory neurons has permitted the age-related changes in the effects of neurotrophins to be interpreted in the appropriate developmental context. In this review I provide a chronological account of the action of neurotrophins in neuronal development with special reference to sensory neurons.

A variety of cytokines, hormones and hematopoietic growth factors signal through the hematopoietin family of membrane receptors, which share several structural features, including a Trp-Ser-X-Trp-Ser motif and four paired cysteine residues. The signal transduction mechanisms utilized by these receptors have remained elusive, although tyrosine kinase activation has been one common element. Recently, a role for the cytoplasmic tyrosine kinases of the Janus kinase (JAK) family has been implicated in signalling by these receptors. There are currently three known JAK family kinases, including JAK1, JAK2 and TYK2. This review will focus on the role of such tyrosine kinases in hematopoietin receptor signal transduction, and address the possibility of the involvement also of unidentified Janus kinases.

The mammalian corpus luteum (CL), which plays a central role in the reproductive process because of its production of hormones such as progesterone, appears to be an exceptionally dynamic organ. Its rate of growth and development are extremely rapid and, even when the CL is functionally mature, its rate of cell turnover remains relatively high. Associated with this high rate of cell turnover, the mature CL receives the greatest blood supply per unit tissue of any organ, and also exhibits a relatively high metabolic rate. Although numerous growth factors have been identified in luteal tissue, their role in growth and differentiation of this dynamic organ remains unclear. Recently, while attempting to identify mitogenic factors of ovine and bovine CL, we have found that they produce several mitogens during the estrous cycle as well as pregnancy. The majority of these luteal-derived mitogenic factors are heparin-binding, and although some may represent previously identified factors, several appear to be novel heparin-binding growth factors. Isolation and purification of mitogenic factors produced by the CL will enable us to determine their roles in luteal growth, development and differentiated function, which will contribute to our understanding not only of the regulation of fertility but also of tissue growth and development in general.

Transforming growth factor β1 (TGF-β1) is the prototype of an increasingly complex superfamily of growth and differentiation factors. To date, a total of 74 TGF-β-like sequences have been published, probably representing 23 distinct genes. These sequences were obtained from mammalian, avian, amphibian and insect species, thus emphasising the ancient nature of the TGF-β superfamily peptides. This article summarises current hypotheses concerning the evolutionary history of this protein superfamily, based on the molecular phylogeny of the published sequences. Comparison of the deduced amino acid sequences leads to the definition of five main groups within the superfamily (TGF-β, Bone Morphogenetic Proteins [BMP], Anti-Müllerian Hormone [AMH], Inhibin α [INHα] and GDF-9) and six subgroups within the BMPs (60A, Decapentaplegic [ddp], Vg1, BMP-3, Inhibin β [$\text{INHβ}{}_{\mathrm{<mtext>A</mtext><mtext>B</mtext>}}$] and nodal). This classification predicts possible phylogenetic and functional relationships among these proteins.

Cytokines are important regulators of hemopoiesis which exert their actions by binding to specific, high affinity, cell surface receptors. In the past several years, molecular cloning of these receptors has revealed a new superfamily referred to as the hemopoietic growth factor receptors. Members of this family are defined by a 200 amino acid conserved domain; however, it has become increasingly apparent that another characteristic of these receptors is the shared usage of a common signalling subunit among subgroups in this family. The shared signalling component explains the functional redundancy of many cytokines; however, the mechanism by which these receptors transduce a signal across the membrane is not yet clear. Studies into cytokine action have shown that many of the events that occur in response to ligand stimulation are similar to those observed for the better characterized intrinsic tyrosine kinase receptors. Thus, although the cytokine receptors do not possess intrinsic tyrosine kinase activity, these observations have led to a model of cytokine signal transduction adapted from the signalling mechanisms described for the tyrosine kinase receptors.

Phosphatidylinositol bisphosphate hydrolysis is an immediate response to many hormones, including growth factors. The hydrolysis of phosphatidylinositol bisphosphate is catalyzed by phosphatidylinositol-specific phospholipase C. A number of phospholipase C isozymes have been identified. Different isozymes are activated by different receptor classes. This review will summarize the different isozymes of phospholipase C, and the current knowledge of the mechanisms by which phospholipase C acitivity is modulated by growth factors.