Mollusk-derived growth factor and the new subfamily of adenosine deaminase-related growth factors.

Peptide and protein growth factors play critical roles in the control of proliferation, differentiation and survival of most, if not all, cell types. In this review, we describe a newly isolated growth factor from Aplysia californica, mollusk derived growth factor (MDGF), that is a member of the adenosine deaminase-related growth factor (ADGF) subfamily. Other known subfamily members from a range of invertebrate and vertebrate species include: insect-derived growth factor, Drosophila ADGFs, tsetse salivary growth factors, insect adenosine deaminases (ADAs; Lutzomyia, Culex, Aedes, Anopheles), and cat eye syndrome critical region gene 1 (CECR1) in humans, pigs, and zebrafish. ADGFs from vertebrates and invertebrates contain both an ADA domain and a novel N-terminal region of about 100 amino acids. Catalytic residues involved in ADA activity are conserved in ADGFs, and inhibitors of ADA can block ADGF activity. ADA enzymatic activity has been shown, by inhibitor and site-directed mutagenesis studies, to be related to the ability of ADGFs from many species to stimulate cell proliferation. The available evidence suggests that the conversion of adenosine to inosine (or their analogs) is important for the mitogenic actions of ADGFs. Future investigations of this novel subfamily should lead to the identification of their receptors.

The family of hepatoma-derived growth factor proteins: characterization of a new member HRP-4 and classification of its subfamilies.

Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of polypeptides named after HDGF, which was identified by its mitogenic activity towards fibroblasts. In the present study, we describe a hitherto unknown HRP, termed HRP-4. The cDNA of bovine HRP-4 (bHRP-4) predicts a polypeptide of 235 amino acids. Northern- and Western-blot analyses of various bovine tissues demonstrated that HRP-4 is only expressed in the testis. Recombinantly produced bHRP-4 and murine HDGF (mHDGF) histidine-tagged polypeptides display growth-factor activity for cultured primary human fibroblasts at an optimum concentration of 1 ng/ml in serum-free medium. The growth-factor activity declines with increasing concentrations to reach background levels at 1 microg/ml. The expression of the fusion proteins, bHRP-4-green fluorescent protein and mHDGF-green fluorescent protein, in HEK-293 cells demonstrates nuclear localization of the proteins. bHRP-4 and mHDGF bind to the glycosaminoglycans heparin and heparan sulphate, but not to chondroitin sulphate. Affinity constants determined for these interactions are between 6 and 42 nM. Comparison of the bHRP-4 amino acid sequence with HRP-1-3 and p52/75/lens epithelium-derived growth factor (LEDGF) shows that these proteins share a conserved N-terminal part of 91 amino acids but have C-termini of different lengths and charge. This demonstrates the modular structure of these proteins and allows its classification into three groups based on charge, size and sequence comparison. HRP-4, HRP-1 and HDGF are small acidic proteins, HRP-3 is a small basic protein, and HRP-2 and p52/75/LEDGF are larger basic proteins.

Nonandrogenic mediators of prostatic growth.

Prostate growth and development are primarily under the control of androgens; however, other factors can also influence prostatic growth through alternative pathways. This article discusses some of the major nonandrogenic mediators of prostate growth. Information on the pathways by which these factors exert their effects is also reviewed.

Molecular cloning of delta-4, a new mouse and human Notch ligand.

Complementary DNAs encoding a previously unidentified mouse Notch ligand and its human ortholog were isolated. The new Notch ligand contains a signal sequence, a DSL domain, eight epidermal growth factor-like repeats, a transmembrane domain, and an intracellular region, all of which are characteristics of members of the Delta protein family. The new protein was therefore designated Delta-4. Several previously unidentified sequences in both the extracellular and intracellular regions were shown to be conserved among vertebrate Delta proteins. The tissue distribution of Delta-4 mRNA resembles that previously described for Notch-4 (Int-3) transcripts. However, in situ hybridization with mouse lung revealed that Delta-4 mRNA is abundant in squamous alveolar cells that neighbor endothelial cells; Notch-4 expression is largely restricted to the latter cell type. Soluble forms of the extracellular portion of Delta-4 inhibit the apparent proliferation of human aortic endothelial cells, but not human pulmonary arterial endothelial cells.

Human colon cancer cell proliferation mediated by the M3 muscarinic cholinergic receptor.

We have demonstrated previously cell surface receptors for gastrointestinal peptides on 10 human colon cancer cell lines. Because most of the cells studied bind muscarinic cholinergic agonists, we undertook the determination of the cholinergic receptor subtype expressed by human colon cancer cells, as well as the biological function of these receptors, and more specifically, the effect on cell proliferation. We used radiolabeled ligand binding, PCR, calcium mobilization, and cellular proliferation studies. The present study demonstrates a muscarinic cholinergic receptor having two classes of binding site for carbamylcholine. Analysis demonstrated 2499+/-153 binding sites/cell, of which 75% had a high affinity for carbamylcholine (Kd 55 microM), and 25% had a low affinity (Kd 0.33 mM). N-Methylscopolamine, a receptor antagonist, recognized only one binding site having high affinity (Kd 0.20 nM). The number of muscarinic cholinergic binding sites/cell found on colon cancer cells is 50% of the number of receptors found on guinea pig chief cells in physiological conditions. Specific cholinergic receptor antagonists inhibit binding in the following order of potency: N-methylscopolamine > 4-DAMP >> pirenzipine > AF-DX116. This order of potency pharmacologically classifies the receptor as an M3 subtype. Receptor expression, studied by reverse transcription-PCR, correlates with the binding data. Specifically, cell lines that exhibit binding, abundantly expressed the M3 receptor subtype, whereas cell lines that do not exhibit binding for muscarinic cholinergic agonists did not abundantly express the M3 receptor. Agonist activation of the M3 receptor on these cells resulted in intracellular calcium mobilization. The dose-response curve of calcium mobilization suggests that there are spare receptors on these cells. Signal transduction can be inhibited by receptor antagonists in the same order of potency in which the binding is inhibited. Exogenous agonist added to the cells in culture induces significant cell proliferation. These results demonstrate a muscarinic cholinergic receptor of the M3 subtype on human colon cancer cells. This receptor induces intracellular calcium mobilization and mediates cell proliferation. The data suggest that there are spare receptors present, and that there may be enhanced intracellular signal activation in response to receptor binding.

Fitoestrógenos: una nueva preocupación en la alimentación infantil / Phytoestrogens: a new preoccupation in paediatric nutrition

Los fitoestrógenos son sustancias ambientales naturales, producidas por plantas, que a pesar de su estructura química distinta de los estrógenos, actúan como tales. Estudios en adultos sugieren que tendrían efectos protectores para cánceres hormonodependientes (de próstata y mama), dislipidemias y de la mineralización ósea. Se clasifican en isoflavonas, cumestanos y lignanos, y se encuentran principalmente en legumbres y poroto de soya, brotes de poroto, forraje y granos, y en cereales de grano entero y semillas, respectivamente. Estudios recientes han demostrado que los alimentos infantiles, incluyendo algunas fórmulas lácteas, yogur y alimentos de soya, contienen cantidades considerables de fitoestrógenos. Los efectos de estos sobre la salud infantil no han sido del todo aclarados. Existen evidencias epidemiológicas y clínicas de que al actuar como estrógenos débiles prodrían determinar adelanto de los eventos puberales y telarquia en la niña y ginecomastia en el varón. Se hace una revisión del tema y se plantea la necesidad de realizar estudios destinados a aclarar los efectos de los estrógenos ambientales sobre la salud infantil

Keratinocytes and cytokine/growth factors.

Cytokines are polypeptide growth factors produced by most nucleated cells in the body, including epithelial cells, keratinocytes, and Langerhans cells in the skin. Cytokines can be classified into interleukins, tumor necrosis factors, chemokines, colony-stimulating factor, interferons, and growth factors. Like classic hormones, cytokines bind to specific receptors to transmit their messages to target cells. Cytokine receptors can be divided into three cytokine receptor superfamilies: the immunoglobulin superfamily, the hematopoietin family, and the tumor necrosis factor family. Following cytokine/cytokine-receptor binding (first messenger), a signal transduction pathway is initiated. Factors affecting homeostasis in the skin and oral mucosa include a delicate balance between cytokines/cytokine-receptors and their antagonists. An imbalance in these variables can influence the development of cutaneous and oral diseases-such as lichen planus, autoimmune disorders, and some neoplastic processes- and can affect wound healing. Potential uses of cytokines include cancer and antiviral therapy.

[Abnormal signal transduction and cancer]. / Transduction anormale du signal et cancer.

Molecules involved in communication and signal transduction play a key role in the control of cell growth and differentiation. Growth factors are multifunctional regulatory peptides acting through membrane receptors, a number of which has tyrosine kinase activity. Downstream, cytoplasmic substrates transduce the signal to the nucleus. This cascade can be altered by structural mutations or by deregulation and thus participate to tumorigenesis.

Adrenomedullin inhibits the secretion of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, from rat alveolar macrophages.

This study was undertaken to determine the effects of adrenomedullin (AM) on the secretion of cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 family, from lipopolysaccharide-stimulated rat alveolar macrophages in vitro. AM significantly increased cAMP levels in alveolar macrophages in a dose-dependent fashion. On the other hand, AM significantly inhibited CINC secretion from alveolar macrophages in a dose-dependent fashion, and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) also significantly inhibited CINC secretion. These findings suggest that AM may play important roles in the regulation of airway inflammation via a cAMP-dependent mechanism.

The cystine-knot growth-factor superfamily.

Four recent crystal structures of growth factors--nerve growth factor, transforming growth factor-beta, platelet-derived growth factor, and human chorionic gonadotropin--from four separate superfamilies revealed that these proteins are structurally related and share a common overall topology. These proteins have very little sequence homology, but they all have an unusual arrangement of six cysteines linked to form a "cystine-knot" conformation. The active forms of these proteins are dimers, either homo- or heterodimers. Despite the overall topological similarity between the monomers, the interfaces used to form the dimer are in each case quite different. Because the surfaces used for dimer formation are mostly hydrophobic, the uniqueness of each dimer accounts for the lack of sequence homology and raises questions about the effectiveness of reverse sequence fitting in this kind of structure as a predictor of structural homology.

Inmunohistoquímica de factores de crecimiento en trabéculos de pacientes glaucomatosos: resultados preliminares en pacientes con glaucoma primario de ángulo abierto / Growth factors' immunohistochemistry in trabecular tissue of glaucoma patients: preliminar results in patients with primary open angle glaucoma

Las alteraciones ultraestructurales en el glaucoma primario de ángulo abierto (GPAA) se relacionan con cambios a nivel celular y de la matriz extracelular en el tejido trabecular y pericanalicular. Los factores de crecimiento (FC) actúan como señales químicas que difunden desde las células produciendo cambios en la composición, estructura y función de la matriz extracelular. El propósito de este estudio fue describir, con la ayuda de la inmunohistoquímica, la presencia de factores de crecimiento y sus receptores en el tejido trabecular. Nuestras observaciones son sugerentes de la presencia de factor de crecimiento fibroblástico (FGF) y de su receptor (FGFr) en células trabeculares de pacientes con GPAA

[Angiogenic role of growth factors]. / Rôle angiogénique des facteurs de croissance.

Several growth factors are potential inducers of neovascularization. This property established from in vitro or in vivo studies suggest that these polypeptides might be involved in physiological angiogenesis. Recent advances in the structure of the growth factors, identification of specific cell surface receptors and in their mechanisms of action bring a better understanding of the biochemical events involved in angiogenesis.

[Growth factors: a pluripotent and misnamed family]. / Les facteurs de croissance: une famille pluripotente et mal nommée.

Growth factors are a family of polypeptides with a major physiological role. They were first described for their mitogenic activity. However, these peptides have a wide spectrum of biological actions which include the regulation of tissue morphology, differentiation, movement and functional activity. They act via an autocrine or paracrine mechanism. They are characterized by their binding to specific receptors at the membrane level. Some of these receptors possess a kinase activity.

The role of growth factors in gastrointestinal cell proliferation.

The epithelial lining of the gastrointestinal (GI) tract is in a state of continuous cell renewal, and the proliferating and differentiating/differentiated cell populations are spatially clearly demarcated. Members of the epidermal growth factor (EGF) family of peptides, the trefoil peptides and enteroglucagon appear to be the most important enterotrophic molecules for both normal cell renewal and healing after cell damage. Transforming growth factor-a (TGF-a) appears to be the primary physiological ligand for the EGF receptor (EGFR), promoting normal cell renewal, and TGF-a/EGFR are part of an autocrine loop in many intestinal cancers. In response to damage, a differentiating cell lineage arises from adjacent epithelium secreting EGF, TGF-a and trefoil peptides; this may be viewed as part of a 'repair kit' in damaged endodermally-derived tissue.