Myosin I: From yeast to human

Myosin I is a non-filamentous, single-headed, actin-binding motor protein and is present in a wide range of species from yeast to man. The role of these class I myosins have been studied extensively in simple eukaryotes, showing their role in diverse processes such as actin cytoskeleton organization, cell motility, and endocytosis. Recently, studies in metazoans have begun to reveal more specialized functions of myosin I. It will be a major challenge in the future to examine the physiological functions of each class I myosin in different cell types of metazoans.     

The Dim protein family: from structure to splicing

The spliceosome is a dynamic macromolecular machine that catalyzes pre-mRNA splicing through a mechanism controlled by several accessory proteins, including the Dim proteins. The Dim protein family is composed of two classes, Dim1 and Dim2, which share a common thioredoxin-like fold. They were originally identified for their role in cell cycle progression and have been found to interact with Prp6, an essential component of the spliceosome, which forms the bridge of U4/U6.U5-tri-snRNP. In spite of their biological and structural similarities, Dim1 and Dim2 proteins differ in many aspects. Dim1 bears distinctive structural motifs responsible for its interaction with other spliceosome components. Dim2 forms homodimers and contains specific domains required for its interactions with partners. This originality suggests that although both proteins are involved in pre-mRNA splicing, they are likely to be involved in different biological pathways. In the present article we review the structure and function of the Dim proteins.     

From endoderm to pancreas: a multistep journey

The formation of the vertebrate pancreas is a complex process that typifies the basic steps of embryonic development. It involves the establishment of competence, specification, signaling from neighboring tissues, morphogenesis, and the elaboration of tissue-specific genetic networks. A full analysis of this multistep process will help us to understand classic principles of embryonic development. Furthermore, this will provide the blueprint for experimental programming of pancreas formation from embryonic stem cells in the context of diabetes cell-therapy. Although in the past decade many studies have contributed to a solid foundation for understanding pancreatogenesis, important gaps persist in our knowledge of early pancreas formation. This review will summarize the current understanding of the early mechanisms coming into play to pattern the "pre-pancreatic" region within the endoderm and, gradually, specify the pancreatic tissue.     

Bile Acids: Chemistry, Pathochemistry, Biology, Pathobiology, and Therapeutics

Bile acids and bile alcohols in the form of their conjugates are amphipathic end products of cholesterol metabolism with multiple physiological functions. The great variety of bile acids and bile alcohols that are present in vertebrates are tabulated. Bile salts have an enterohepatic circulation resulting from efficient vectorial transport of bile salts through the hepatocyte and the ileal enterocyte; such transport leads to the accumulation of a pool of bile salts that cycles between the liver and intestine. Bile salt anions promote lipid absorption, enhance tryptic cleavage of dietary proteins, and have antimicrobial effects. Bile salts are signaling molecules, activating nuclear receptors in the hepatocyte and ileal enterocyte, as well as an increasing number of G-protein coupled receptors. Bile acids are used therapeutically to correct deficiency states, to decrease the cholesterol saturation of bile, or to decrease the cytotoxicity of retained bile acids in cholestatic liver disease.     

Physiological functions of D-amino acid oxidases: from yeast to humans

D-Amino acid oxidase (DAAO) is a FAD-containing flavoenzyme that catalyzes the oxidative deamination of D-isomers of neutral and polar amino acids. This enzymatic activity has been identified in most eukaryotic organisms, the only exception being plants. In the various organisms in which it does occur, DAAO fulfills distinct physiological functions: from a catabolic role in yeast cells, which allows them to grow on D-amino acids as carbon and energy sources, to a regulatory role in the human brain, where it controls the levels of the neuromodulator D-serine. Since 1935, DAAO has been the object of an astonishing number of investigations and has become a model for the dehydrogenase-oxidase class of flavoproteins. Structural and functional studies have suggested that specific physiological functions are implemented through the use of different structural elements that control access to the active site and substrate/product exchange. Current research is attempting to delineate the regulation of DAAO functions in the contest of complex biochemical and physiological networks.     

Loss of FrmA leads to increased cell-cell adhesion and impaired multi-cellular development of Dictyostelium cells

Cell-cell adhesion is a critical property of all multi-cellular organisms and its correct regulation is critical during development, differentiation, tissue building and maintenance, and many immune responses. The multi-talin-like FERM domain containing protein, FrmA, is required during starvation-induced multi-cellular development of Dictyostelium cells. Loss of FrmA leads to increased cell-cell adhesion and results in impaired multi-cellular development, slug migration and fruiting bodies. Further, mixing experiments show that FrmA null cells are excluded from the apex of wild-type mounds, to which cells that normally form the organising centre known as the tip sort. These data suggest a critical role for FrmA in regulating cell-cell adhesion, multi-cellular development and, in particular, the formation of the organising centre known as the tip. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 28 August 2008; received after revision 10 October 2008; accepted 21 October 2008     

Proliferating cell nuclear antigen: a proteomics view

Proliferating cell nuclear antigen (PCNA), a cell cycle marker protein, is well known as a DNA sliding clamp for DNA polymerase delta and as an essential component for eukaryotic chromosomal DNA replication and repair. Due to its mobility inside nuclei, PCNA is dynamically presented in a soluble or chromatin-associated form. The heterogeneity and specific modifications of PCNA may reflect its multiple functions and the presence of many binding partners in the cell. The recent proteomics approaches applied to characterizing PCNA interactions revealed multiple PCNA partners with a wide spectrum of activity and unveiled the possible existence of new PCNA functions. Since more than 100 PCNA-interacting proteins and several PCNA modifications have already been reported, a proteomics point of view seems exactly suitable to better understand the role of PCNA in cellular functions. Received 29 May 2008; received after revision 7 July 2008; accepted 16 July 2008     

The bugs that came in from the cold: molecular adaptations to low temperatures in insects

The widespread distribution of insects over many ecological niches is a testimony to their evolutionary success. The colonization of environments at high latitudes or altitudes required the evolution of biochemical strategies that reduced the impact of cold or freezing stress. This review focuses on our current interests in some of the genes and proteins involved in low temperature survival in insects. Although the most widespread form of protection is the synthesis of low molecular weight polyol cryoprotectants, proteins with intrinsic protective properties, such as the thermal hysteresis or antifreeze proteins are also important. These have been cloned and characterized in certain moths and beetles. Molecular techniques allowing the isolation of genes differentially regulated by low temperatures have revealed that heat shock proteins, cold stress proteins, membrane protectants, as well as ice nucleators and other less well characterized proteins likely also play a role in cold hardiness. Received 10 June 2008; received after revision 17 November 2008; accepted 18 November 2008     

The Role of the Agouti-Related Protein in Energy Balance Regulation

The Agouti-Related Protein (AgRP) is a powerful orexigenic peptide that increases food intake when ubiquitously overexpressed or when administered centrally. AgRP-deficiency, on the other hand, leads to increased metabolic rate and a longer lifespan when mice consume a high fat diet. In humans, AgRP polymorphisms have been consistently associated with resistance to fatness in Blacks and Whites and resistance to the development of type-2 diabetes in African Blacks. Systemically administered AgRP accumulates in the liver, the adrenal gland and fat tissue while recent findings suggest that AgRP may also have inverse agonist effects, both centrally and peripherally. AgRP could thus modulate energy balance via different actions. Its absence or reduced functionality may offer a benefit both in terms of bringing about negative energy balance in obesigenic environments, as well as leading to an increased lifespan.     

Erythropoietins from teleosts

The epo genes of many teleosts, including zebrafish, have been cloned following the first identification of nonmammalian EPO from fugu in 2004. The zebrafish (Danio rerio) animal model is well suited for both developmental and genetic analyses for studying vertebrate erythropoiesis. The purpose of this review is to provide an update of recent progress in research on teleost EPO with a focus on its structure, expression and secretion. The EPO receptor and the downstream JAK/STAT signaling pathway are also discussed. Received 29 April 2008; received after revision 23 June 2008; accepted 25 June 2008     

Curcumin: From ancient medicine to current clinical trials

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.     

Physiological arousal: a role for hypothalamic systems

The lateral hypothalamus (LH) has long been known as a homeostasis center of the brain that modulates feeding behavior, arousal and reward. The hypocretins (Hcrts, also called orexins) and melanin-concentrating hormone (MCH) are neuropeptides produced in two intermingled populations of a few thousand neurons in the LH. The Hcrts have a prominent role in regulating the stability of arousal, since Hcrt system deficiency leads to narcolepsy. MCH is an important modulator of energy balance, as MCH system deficiency in mice leads to leanness and increased metabolism. Recently, MCH has been proposed to modulate rapid eye movement sleep in rodents. In this review, we propose a working model of the cross-talk between Hcrt and MCH circuits that may provide an arousal balance system to regulate complex goal-oriented behaviors.     

High molecular weight FGF2: the biology of a nuclear growth factor

Fibroblast growth factor 2 (FGF2) is one of the most studied growth factors to date. Most attention has been dedicated to the smallest, 18kDa FGF2 variant that is released by cells and acts through activation of cell-surface FGF-receptor tyrosine kinases. There are, however, several higher molecular weight (HMW) variants of FGF2 that rarely leave their producing cells, are retained in the nucleus and act independently of FGF-receptors (FGFR). Despite significant evidence documenting the expression and intracellular trafficking of HMW FGF2, many important questions remain about the physiological roles and mechanisms of action of HMW FGF2. In this review, we summarize the current knowledge about the biology of HMW FGF2, its role in disease and areas for future investigation. Received 28 July 2008; received after revision 18 August 2008; accepted 22 August 2008     

Stem cell therapy in stroke

Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects. Received 23 June 2008; received after revision 24 September 2008; accepted 30 September 2008