Signal transduction and regulation of neurotrophins.

Our understanding of the molecular nature of neurotrophic interactions has been greatly enhanced by the recent isolation and characterization of several new neurotrophic factors and their receptors. Neurotrophic factors have been found to be regulated by neuronal activity in the central nervous system, and may be involved in activity-dependent processes throughout development and maturity.     

Aberrant regulation of translation initiation in tumorigenesis

Altering the rate of translation initiation of a specific gene can tightly regulate the synthesis of the corresponding polypeptide and is an important mechanism in the control of gene expression. For some time it has been known that many genes involved in cell proliferation, cell growth and apoptosis have atypical 5' untranslated regions (UTRs) containing a high degree of RNA secondary structure, upstream open reading frames and internal ribosome entry segments. These features play a key role in the regulation of protein synthesis. In this review we discuss how the rate of translation initiation of proto-oncogenes and tumour suppressor genes is affected by elements in their 5' and 3' UTRs and we focus on how changes in the controlof gene expression at this level can contribute towards tumorigenesis.     

Signal transduction and virulence regulation in human and animal pathogens

Abstract Pathogens have developed many strategies for survival in animals and humans which possess very effective defense mechanisms. Although there are many different ways, in which pathogenic bacteria solved the problem to overcome the host defense, some common features of virulence mechanisms can be detected even in phylogenetically very distant bacteria (Finlay and Falkow (1989) Microb. Rev. 6 1375–1383). One important feature is that the regulation of expression of virulence factors and the exact timing of their expression is very important for many of the pathogenic bacteria, as most of them have to encounter different growth situations during an infection cycle, which require a fast adaptation to the new situation by the expression of different factors. This review gives an overview about the mechanisms used by pathogenic bacteria to accomplish the difficult task of regulation of their virulence potential in response to environmental changes. In addition, the relationship of these virulence regulatory systems with other signal transduction mechanisms not involved in pathogenicity is discussed.     

平滑肌收缩调节的信号转导

平滑肌细胞内信号转导主要有肌球蛋白轻链激酶（ＭＬＣＫ）和蛋白激酶Ｃ（ＰＫＣ）途径。前者通过肌浆内Ｃａ＾２＋浓度升高,激活钙调蛋白（ＣａＭ）依赖性ＭＬＣＫ,催化肌球蛋白轻链丝氨酸（Ｓｅｒ）－１９磷酸化,肌球蛋白ＡＴＰ酶活性增加,肌丝滑行,肌肉收缩。肌浆内Ｃａ＾２＋浓度的恢复使ＭＬＣＫ失活,肌球蛋白轻链磷酸酶（ＭＬＣＰ）使肌球蛋白脱磷酸化,肌肉舒张。近来有证据表明ＰＫＣ信号转导途径通过影响细肌丝相关蛋     

Signal transduction mechanisms in the regulation of protein synthesis

Control of polypeptide synthesis plays an important role in cell proliferation and translation rates generally reflect the growth state of the cultured eukaryotic cell. Physiological regulation of protein synthesis is almost always exerted at the level of polypeptide chain initiation, with the binding of mRNA to the small ribosomal subunit a rate-limiting step in many cell systems. Studies have indicated key roles in the regulation of protein synthesis for the structural features of mRNA molecules and phosphorylation of initiation factors which catalyse this process. This review focusses on translational regulation at the level of mRNA binding to the ribosome and the role of phosphorylation of initiation factors in mediating both quantitative and qualitative control. The identity of putative kinases which may mediate these processes is addressed and a possible model for the role of a transient activation of initiation factors in cell growth or differentiation is presented.     

The roles of translation initiation regulation in ultraviolet light-induced apoptosis

Ultraviolet light (UV) inhibits translation initiation through activation of kinases that phosphorylate the α-subunit of eukaryotic initiation factor 2 (eIF2α). Two eIF2α kinases, PERK and GCN2, are known to phosphorylate the Serine-51 of eIF2α in response to UV-irradiation. In this report, we present evidence that phosphorylation of eIF2α plays a role in UV-induced apoptosis. Our data show that wild-type mouse embryo fibroblasts (MEF^s/s) are less sensitive to UV-induced apoptosis than MEF^A/A cells in which the phosphorylation site, Ser51, of eIF2α is replaced with a non-phosphorylatable Ala (Ser51Ala). PARP expression in MEF^A/A cells is reduced without being cleaved after UV-irradiation. In contrast, PARP is cleaved without a significant decrease in parental PARP in MEF^S/S cells after UV-irradiation. Our data also show that MEF^GCN2−/− cells, in which GCN2 is knocked out, are more sensitive to UV-irradiation, agreeing with the observation from MEF^A/A cells. However, MEF^PERK−/− cells, in which PERK is knocked out, are less sensitive to UV-irradiation. In addition, MCF-7-PERKΔC cells, which are stably transfected with a kinase domain deleted mutant of PERK (PERKΔC), are more resistant to UV-induced apoptosis than parental MCF-7 cells. Overexpression of wild-type PERK sensitizes MCF-7 cells to UV-induced apoptosis without directly inducing cell death. These results suggest that the level of eIF2α phosphorylation impacts PARP expression upon UV-irradiation. The eIF2α kinases may mediate UV-induced apoptosis via an eIF2α dependent or independent signaling pathway.     

Signal transduction and the regulation of apoptosis: roles of ceramide

Knowledge about the molecular regulators of apoptosis is rapidly expanding. Cell death signals emanating from death receptors or internal cell injury detectors launch a number of signaling pathways which converge on several key families of proteins including specialized proteases and endonucleases which play a critical role in the execution of the death order. In this review, we summarize recent discoveries relating to the signaling pathways involved, the death receptors, the caspase family of apoptotic proteases, Bcl-2 family members, the sphingolipid ceramide, and the tumor suppressor p53. In particular, we focus on the role played by ceramide as a coordinator of the stress response and as a candidate biostat in the detection of cell injury.     

Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases.     

Signal transduction in erythropoiesis.

The polypeptide hormone erythropoietin (Ep) is a growth factor whose actions on the erythroid progenitor cell induce proliferation and differentiation. The signal transduction system activated by Ep to mediate these cellular processes remains largely uncharacterized despite many years of research devoted to its elucidation. It is clear that an Ep receptor-mediated activation of adenylate cyclase or guanylate cyclase does not occur, although cAMP and cGMP may play modulatory roles. The role of calcium in the action of Ep is less clear. Although the presence of extracellular calcium seems to be an absolute requirement for Ep-induced proliferation, the positive changes induced by Ep in intracellular calcium occur with a time course suggestive of influx through ion channels opening within the cell membrane rather than release of intracellular stores by inositol trisphosphate. There is good evidence for the involvement of phospholipases A2 and C in the actions of Ep, including an early rise in lipoxygenase metabolites of arachidonic acid. Activation of phospholipase C can also result in the activation of protein kinase C in response to Ep. We present a model for the signal transduction pathway of Ep that is consistent with current knowledge and provides a framework for the coordinate actions of several intracellular mechanisms in the mediation of Ep-induced proliferation.     

Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation

The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation was that FSH regulates proliferation through a PI3K/Akt/mTORC1 pathway, and additionally, AMPK-dependent mechanisms counteract FSH proliferative effects. The present study was performed in 8-day-old rat Sertoli cell cultures. The results presented herein show that FSH, in addition to increasing p-Akt, p-mTOR, and p-p70S6K levels, increases p-PRAS40 levels, probably contributing to improving mTORC1 signaling. Furthermore, the decrease in FSH-stimulated p-Akt, p-mTOR, p-p70S6K, and p-PRAS40 levels in the presence of wortmannin emphasizes the participation of PI3K in FSH signaling. Additionally, the inhibition of FSH-stimulated Sertoli cell proliferation by the effect of wortmannin and rapamycin point to the relevance of the PI3K/Akt/mTORC1 signaling pathway in the mitotic activity of FSH. On the other hand, by activating AMPK, several interesting observations were made. Activation of AMPK produced an increase in Raptor phosphorylation, a decrease in p70S6K phosphorylation, and a decrease in FSH-stimulated Sertoli cell proliferation. The decrease in FSH-stimulated cell proliferation was accompanied by an increased expression of the cyclin-dependent kinase inhibitors (CDKIs) p19INK4d, p21Cip1, and p27Kip1. In summary, it is concluded that FSH regulates Sertoli cell proliferation with the participation of a PI3K/Akt/mTORC1 pathway and that AMPK activation may be involved in the detention of proliferation by, at least in part, a decrease in mTORC1 signaling and an increase in CDKI expression.     

Bypassing translation initiation

A high-resolution cryo-EM reconstruction of a ribosome-bound dicistrovirus IRES (Schüler et al., 2006) and the crystal structure of its ribosome binding domain (Pfingsten et al., 2006) provide new insights into an exceptional eukaryotic translation mechanism.