Activation and inactivation of thyroid hormone by deiodinases: Local action with general consequences

The thyroid hormone plays a fundamental role in the development, growth, and metabolic homeostasis in all vertebrates by affecting the expression of different sets of genes. A group of thioredoxin fold-containing selenoproteins known as deiodinases control thyroid hormone action by activating or inactivating the precursor molecule thyroxine that is secreted by the thyroid gland. These pathways ensure regulation of the availability of the biologically active molecule T3, which occurs in a time-and tissue-specific fashion. In addition, because cells and plasma are in equilibrium and deiodination affects central thyroid hormone regulation, these local deiodinase-mediated events can also affect systemic thyroid hormone economy, such as in the case of non-thyroidal illness. Heightened interest in the field has been generated following the discovery that the deiodinases can be a component in both the Sonic hedgehog signaling pathway and the TGR-5 signaling cascade, a G-protein-coupled receptor for bile acids. These new mechanisms involved in deiodinase regulation indicate that local thyroid hormone activation and inactivation play a much broader role than previously thought. Received 29 August 2007; received after revision 11 October 2007; accepted 16 October 2007     

Thyroid hormone actions in liver cancer

The thyroid hormone 3,3′,5-triiodo-l-thyronine (T₃) mediates several physiological processes, including embryonic development, cellular differentiation, metabolism, and the regulation of cell proliferation. Thyroid hormone receptors (TRs) generally act as heterodimers with the retinoid X receptor (RXR) to regulate target genes. In addition to their developmental and metabolic functions, TRs have been shown to play a tumor suppressor role, suggesting that their aberrant expression can lead to tumor transformation. Conversely, recent reports have shown an association between overexpression of wild-type TRs and tumor metastasis. Signaling crosstalk between T₃/TR and other pathways or specific TR coregulators appear to affect tumor development. Since TR actions are complex as well as cell context-, tissue- and time-specific, aberrant expression of the various TR isoforms has different effects during diverse tumorigenesis. Therefore, elucidation of the T₃/TR signaling mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a summary of recent studies focusing on the role of TRs in hepatocellular carcinomas (HCCs).     

Gonadotrophin-releasing activity of histones H2A and H2B

We report that histones H2A and H2B possess gonadotrophin-releasing activity in vitro and assess the signal transduction pathways involved in these effects. Perifused and incubated rat anterior pituitary (AP) cells were used, and luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured by RIA. Perifusion of cells with histone H2A (30 μM) or histone H2B (30 μM), markedly stimulated LH release but failed to elicit any FSH response. Cells incubated with 6 or 30 μM histone H2A showed a dose- and time-dependent stimulatory effect on both LH and FSH release which was blocked by 1 μM peptide MB35, an 86–120 amino acid fragment of histone H2A. Incubation of pituitary cells with gonadotrophin-releasing hormone (GnRH) and histones H2A or H2B showed a stimulatory effect on LH and FSH release which was similar to the sum of the separate effects. Trifluoperazine, as well as ethylene glycol bis(b-aminoethyl ether) N,N,N′,N′-tetraacetic acid (EGTA), alone or in the presence of the calcium ionophore A23187, significantly reduced the response of AP cells to histones. Various cyclic adenosine monophosphate (cAMP) enhancers had no effect on histone-stimulated release of gonadotrophins in incubated AP cells. Our results confirm previous evidence that histones may act as hypophysiotrophic signals. Calcium- and diacylglycerol-associated pathways, but not cAMP, appear to participate in these effects. Received 11 August 1997; received after revision 20 January 1998; accepted 26 January 1998     

Dual action of the active oxygen species during plant stress responses

Adaptation to environmental changes is crucial for plant growth and survival. However, the molecular and biochemical mechanisms of adaptation are still poorly understood and the signaling pathways involved remain elusive. Active oxygen species (AOS) have been proposed as a central component of plant adaptation to both biotic and abiotic stresses. Under such conditions, AOS may play two very different roles: exacerbating damage or signaling the activation of defense responses. Such a dual function was first described in pathogenesis but has also recently been demonstrated during several abiotic stress responses. To allow for these different roles, cellular levels of AOS must be tightly controlled. The numerous AOS sources and a complex system of oxidant scavengers provide the flexibility necessary for these functions. This review discusses the dual action of AOS during plant stress responses.     

The role of inflammation in sporadic and familial Parkinson’s disease

The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions.     

Genetic studies of diseases

Pancreatitis is usually inflammation of the pancreas without infection. Our understanding of pancreatitis has been built on autopsy studies, surgical biopsies and surrogate markers of inflammation and fibroses, including abdominal imaging techniques and pancreatic functional studies. However, the discovery that a number of different environmental factors and various genetic abnormalities are seen in patients with similar appearing pancreatitis phenotypes teaches us that end-stage pathology is not the disorder. Understanding complex associations and interactions requires that the components and their interactions be organized, stratified and functionally defined. Systems biology, in the broad sense, provides the approach and tools to define the complex mechanisms driving pathology. As the mathematics behind these pathways and mechanisms are defined and calibrated, the potential pathology of patients with early signs of disease can be predicted, and a number of patient-specific targets for intervention can be defined.     

Developmental regulation of p70 S6 kinase by a G protein-coupled receptor dynamically modelized in primary cells

The mechanisms whereby G protein-coupled receptors (GPCR) activate signalling pathways involved in mRNA translation are ill-defined, in contrast to tyrosine kinase receptors (TKR). We compared a GPCR and a TKR, both endogenously expressed, for their ability to mediate phosphorylation of 70-kDa ribosomal S6 kinase p70S6K in primary rat Sertoli cells at two developmental stages. In proliferating cells stimulated with follicle-stimulating hormone (FSH), active p70S6K was phosphorylated on T389 and T421/S424, through cAMP-dependent kinase (PKA) and phosphatidyl-inositide-3 kinase (PI3K) antagonizing actions. In FSH-stimulated differentiating cells, active p70S6K was phosphorylated solely on T389, PKA and PI3K independently enhancing its activity. At both developmental stages, insulin-induced p70S6K regulation was consistent with reported data. Therefore, TKR and GPCR trigger distinct p70S6K active conformations. p70S6K developmental regulation was formalized in a dynamic mathematical model fitting the data, which led to experimentally inaccessible predictions on p70S6K phosphorylation rate.     

Adenyl cyclase activity at different environmental temperatures in the isolated rat anterior pituitary membranes.

The effect of different environmental temperatures on adenyl cyclase was studied. An increase in temperature appears to increase TRH-induced activity of adenyl cyclase, and possible causes an increases sensitivity to the hormone. Cyclic AMP levels of the pituitaries showed change at different environmental temperatures.     

Adenyl cyclase activity at different environmental temperatures in the isolated rat anterior pituitary membranes

Summary The effect of different environmental temperatures on adenyl cyclase was studied. An increase in temperature appears to increase TRH-induced activity of adenyl cyclase, and possibly causes an increased sensitivity to the hormone. Cyclic AMP levels of the pituitaries showed change at different environmental temperatures.     

Bacterial chemoreceptors and chemoeffectors

Bacteria use chemotaxis signaling pathways to sense environmental changes. Escherichia coli chemotaxis system represents an ideal model that illustrates fundamental principles of biological signaling processes. Chemoreceptors are crucial signaling proteins that mediate taxis toward a wide range of chemoeffectors. Recently, in deep study of the biochemical and structural features of chemoreceptors, the organization of higher-order clusters in native cells, and the signal transduction mechanisms related to the on–off signal output provides us with general insights to understand how chemotaxis performs high sensitivity, precise adaptation, signal amplification, and wide dynamic range. Along with the increasing knowledge, bacterial chemoreceptors can be engineered to sense novel chemoeffectors, which has extensive applications in therapeutics and industry. Here we mainly review recent advances in the E. coli chemotaxis system involving structure and organization of chemoreceptors, discovery, design, and characterization of chemoeffectors, and signal recognition and transduction mechanisms. Possible strategies for changing the specificity of bacterial chemoreceptors to sense novel chemoeffectors are also discussed.     

The role of estrogen receptor α in the regulation of bone and growth plate cartilage

Estrogens are important endocrine regulators of skeletal growth and maintenance in both females and males. Studies have demonstrated that the estrogen receptor (ER)-α is the main mediator of these estrogenic effects in bone. Therefore, estrogen signaling via ERα is a target both for affecting longitudinal bone growth and bone remodeling. However, treatment with estradiol (E2) leads to an increased risk of side effects such as venous thromboembolism and breast cancer. Thus, an improved understanding of the signaling pathways of ERα will be essential in order to find better bone specific treatments with minimal adverse effects for different estrogen-related bone disorders. This review summarizes the recent data regarding the intracellular signaling mechanisms, in vivo, mediated by the ERα activation functions (AFs), AF-1 and AF-2, and the effect on bone, growth plate and other estrogen responsive tissues. In addition, we review the recent cell-specific ERα-deleted mouse models lacking ERα specifically in neuronal cells or growth plate cartilage. The newly characterized signaling pathways of estrogen, described in this review, provide a better understanding of the ERα signaling pathways, which may facilitate the design of new, bone-specific treatment strategies with minimal adverse effects.     

Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle

Vascular smooth muscle tone is controlled by a balance between the cellular signaling pathways that mediate the generation of force (vasoconstriction) and release of force (vasodilation). The initiation of force is associated with increases in intracellular calcium concentrations, activation of myosin light-chain kinase, increases in the phosphorylation of the regulatory myosin light chains, and actin-myosin crossbridge cycling. There are, however, several signaling pathways modulating Ca²⁺ mobilization and Ca²⁺ sensitivity of the contractile machinery that secondarily regulate the contractile response of vascular smooth muscle to receptor agonists. Among these regulatory mechanisms involved in the physiological regulation of vascular tone are the cyclic nucleotides (cAMP and cGMP), which are considered the main messengers that mediate vasodilation under physiological conditions. At least four distinct mechanisms are currently thought to be involved in the vasodilator effect of cyclic nucleotides and their dependent protein kinases: (1) the decrease in cytosolic calcium concentration ([Ca²⁺]c), (2) the hyperpolarization of the smooth muscle cell membrane potential, (3) the reduction in the sensitivity of the contractile machinery by decreasing the [Ca²⁺]c sensitivity of myosin light-chain phosphorylation, and (4) the reduction in the sensitivity of the contractile machinery by uncoupling contraction from myosin light-chain phosphorylation. This review focuses on each of these mechanisms involved in cyclic nucleotide-dependent relaxation of vascular smooth muscle under physiological conditions.     

Nanocarriers’ entry into the cell: relevance to drug delivery

Nanocarriers offer unique possibilities to overcome cellular barriers in order to improve the delivery of various drugs and drug candidates, including the promising therapeutic biomacromolecules (i.e., nucleic acids, proteins). There are various mechanisms of nanocarrier cell internalization that are dramatically influenced by nanoparticles’ physicochemical properties. Depending on the cellular uptake and intracellular trafficking, different pharmacological applications may be considered. This review will discuss these opportunities, starting with the phagocytosis pathway, which, being increasingly well characterized and understood, has allowed several successes in the treatment of certain cancers and infectious diseases. On the other hand, the non-phagocytic pathways encompass various complicated mechanisms, such as clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis, which are more challenging to control for pharmaceutical drug delivery applications. Nevertheless, various strategies are being actively investigated in order to tailor nanocarriers able to deliver anticancer agents, nucleic acids, proteins and peptides for therapeutic applications by these non-phagocytic routes.     

Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer

TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL’s ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL’s potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents.     

An overview of cancer multidrug resistance: a still unsolved problem

Although various mechanisms involved in anticancer multidrug resistance (MDR) can be identified, it remains a major problem in oncology. Beyond that, the introduction of new “targeted” drugs have not solved the problem. On the contrary, it has been demonstrated that the “classical” MDR-associated mechanisms are similar or identical to those causing resistance to these novel agents. These mechanisms include the enhanced activity of drug pumps, i.e. ABC or alternative transporters; modulation of cellular death pathways; alteration and repair of target molecules; and various less common mechanisms. Together they build a complex network of cellular pathways and molecular mechanisms mediating an individual MDR phenotype. Although the application of new high throughput “-omics” technologies have identified multiple new gene-/protein expression signatures or factors associated with drug resistance, so far none of these findings has been useful for creating improved diagnostic assays, for prediction of individual therapy response, or for development of updated chemosensitizers. Received 05 March 2008; received after revision 21 May 2008; accepted 23 May 2008