p53 and TGF-beta in development: prelude to tumor suppression?

Recent work in Xenopus embryos reveals an unexpected developmental role for the tumor suppressor gene p53. This finding may have implications for the evolution of p53, its interaction with Smads in TGF-beta dependent mesoderm specification, and the cooperation among p53 family members.     

Maintaining the immunological balance in parasitic infections: a role for TGF-beta?

Transforming growth factor beta (TGF-beta) is an important regulator of inflammation, being proinflammatory at low concentrations and anti-inflammatory at high concentrations. As such, TGF-beta might be important in maintaining the balance between control and clearance of infectious organisms on the one hand and prevention of immune-mediated pathology on the other. In this article, Fakhereldin Omer, J?rgen Kurtzhals and Eleanor Riley review the immunoregulatory properties of TGF-beta in the context of parasitic infections. Data from murine malaria infections suggest that TGF-beta modifies the severity of the disease, and a number of potential protective mechanisms are discussed. Evidence is accumulating that TGF-beta is important for the regulation of other host-parasite interactions and that parasites might directly influence TGF-beta-dependent pathways via the synthesis of TGF-beta or TGF-beta-receptor homologues.     

Does heme oxygenase-1 have a role in Caco-2 cell cycle progression?

Intestinal epithelium undergoes a rapid self-renewal process characterized by the proliferation of the crypt cells, their differentiation into mature enterocytes as they migrate up to the villi, followed by their shedding as they become senescent villus enterocytes. The exact mechanism that regulates the intestinal epithelium renewal process is not well understood, but the differential expression of regulatory genes along the crypt-villus axis may have a role. Heme oxygenase-1 (HO-1) is involved in endothelial cell cycle progression, but its role in the intestinal epithelial cell turnover has not been explored. With its effects on cell proliferation and its differential expression along the crypt-villus axis, HO-1 may play a role in the intestinal epithelial cell renewal process. In this study, we examined the role of HO-1 in the proliferation and differentiation of Caco-2 cells, a well-established in vitro model for human enterocytes. After confluence, Caco-2 cells undergo spontaneous differentiation and mimic the crypt to villus maturation observed in vivo. In preconfluent and confluent Caco-2 cells, HO-1 protein expression was determined with the immunoblot. HO-1 activity was determined by the ability of the enzyme to generate bilirubin from hemin. The effect of a HO-1 enzyme activity inhibitor, tin protoporphyrin (SnPP), on Caco-2 cell proliferation and differentiation was examined. In preconfluent cells, cell number was determined periodically as a marker of proliferation. Cell viability was measured with MTT assay. Cell differentiation was assessed by the expression of a brush border enzyme, alkaline phophatase (ALP). HO-1 was expressed in subconfluent Caco-2 cells and remained detectable until 2 days postconfluency. This timing was consistent with cells starting their differentiation and taking the features of normal intestinal epithelial cells. HO-1 was inducible in confluent Caco-2 cells by the enzyme substrate, hemin in a dose- and time-dependent manner. SnPP decreased the cell number and viability of preconfluent cells and delayed the ALP enzyme activity of confluent cells. HO-1 may be involved in intestinal cell cycle progression.     

Tumour progression and cancer-induced pain: A role for protease-activated receptor-2?

The role of proteases in modifying the microenvironment of tumour cells has long been recognised. With the discovery of the protease-activated receptor family of G protein-coupled receptors a mechanism for cells to sense and respond directly to proteases in their microenvironment was revealed. Many early studies described the roles of protease-activated receptors in the cellular events that occur during blood coagulation and inflammation. More recently, studies have begun to focus on the roles of protease-activated receptors in the establishment, progression and metastasis of a variety of tumours. This review will focus on the expression of protease-activated receptor-2 and its activators by normal and neoplastic tissues, and describe current evidence that activation of protease-activated receptor-2 is an important event at multiple stages of tumour progression and in pain associated with cancer.     

Trypanosomiasis and trypanotolerance in cattle: a role for congopain?

A Trypanosoma congolense cysteine protease (congopain) elicits a high IgG response in trypanotolerant but not in trypanosusceptible cattle during primary infections. As discussed here by Edith Authié, this observation suggests that congopain, like other parasite cysteine proteases, may play a role in pathogenicity and that more efficient immune responses to congopain may contribute to trypanotolerance.     

Plant fructan exohydrolases: a role in signaling and defense?

Fructans are fructose oligomers and polymers synthesized by a small number of plant and bacterial species and mainly function as reserve carbohydrates. The terminal fructosyl-fructose linkages can be degraded by fructan exohydrolases (FEHs), occurring in bacteria, fungi and fructan plants. Unexpectedly, it was found that FEHs also occur in non-fructan plants such as Beta vulgaris and Arabidopsis thaliana that apparently lack endogenous fructan substrates. FEHs might have defense-related roles acting on bacterial fructan-containing slimes or might act on minute (up to now undetected) amounts of fructans acting as signals in plants.     

Tumor-associated fibroblasts (part I): Active stromal participants in tumor development and progression?

Phenotypic and functional characteristics of tumor associated fibroblasts (TAF) in contrast to normal fibroblasts are reviewed in this first synopsis (part I). Terms as tumor stroma, desmo-plasia, TAF, myofibroblast, and fetal-type fibroblast are defined, and experimental systems to study heterologous cell interactions are presented. While we only start to gather information on the genotype of TAF, a broad range of data deals with the expression profile of these cells, covering e.g. ECM and ECM-modulating molecules, growth factors and cytokines. Summarizing the recent state of knowledge indicates that TAF provide sources for tumor diagnosis and therapy, that have to be further defined in an organ-specific approach in terms of the functional impact on the tumor cell and its environment (see part II).     

Th17 cells: positive or negative role in tumor?

Th17 cells have been recently identified as a distinct Th cell lineage and found in an experimental animal model of cancer and in human cancers, but whether these cells promote tumor growth or regulate antitumor responses remains controversial. This review provides a summary of the current literature regarding interleukin (IL)-17/IL-23 and Th17 cells in cancer and discusses their potential roles in cancer development. Finally, we note several issues in this research area that must be resolved before the design of novel therapeutic approaches specifically targeting Th17 cells in cancer become feasible.     

Lipoproteins and mitogen-activated protein kinase signaling: a role in atherogenesis?

PURPOSE OF REVIEW: Lipoproteins play a critical role in the development of atherosclerosis, which might result partly from their capacity to induce specific intracellular signaling pathways. The goal of this review is to summarize the signaling properties of lipoproteins, in particular, their capacity to induce activation of mitogen-activated protein kinase pathways and the resulting modulation of cellular responses in blood vessel cells. RECENT FINDINGS: Lipoproteins activate the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in all blood vessel cell types. This may require lipoprotein docking to scavenger receptor B1, allowing transfer of cholesterol and sphingosine-1-phosphate to plasma membranes. Subsequent propagation of the signals probably requires the stimulation of G protein-coupled receptors, followed by the transactivation of receptor tyrosine kinases. Lipoprotein-induced extracellular signal-regulated kinase activity favors cell proliferation, whereas lipoprotein-induced p38 mitogen-activated protein kinase activity leads to cell hyperplasia and promotes cell migration. Some signaling pathways and cellular effects induced by lipoproteins have been observed in atherosclerotic plaques and therefore represent potential targets for the development of anti-atherosclerotic drugs. SUMMARY: The main blood vessel cell types have the capacity to activate protein kinase pathways in the presence of lipoproteins. This induces cell proliferation, hyperplasia and migration, known to be dysregulated in atherosclerotic lesions.     

Hybridization and speciation in angiosperms: a role for pollinator shifts?

The majority of convincingly documented cases of hybridization in angiosperms has involved genetic introgression between the parental species or formation of a hybrid species with increased ploidy; however, homoploid (diploid) hybridization may be just as common. Recent studies, including one in BMC Evolutionary Biology, show that pollinator shifts can play a role in both mechanisms of hybrid speciation.     

Is there a malignant progression associated with a linear change in protein expression levels from normal canine mammary gland to metastatic mammary tumors?

The molecular mechanisms of the development of canine mammary tumors are still incompletely understood. In the present study we hypothesized that there is a malignant progression from normal gland to malignant carcinomas that is associated with a linear change in protein expression. To this end, the proteome of canine normal mammary gland, adenomas, nonmetastatic carcinomas, and metastatic carcinomas was compared. Application of 2D-DIGE and MALDI-TOF-MS identified 48 proteins with significant changes (fold change >|1.5|; p < 0.05) in expression levels at the different stages of malignant progression. Forty-two of these followed three major stepwise but not linear expression patterns. Thirteen proteins showed the adenoma pattern characterized by a change in protein expression levels during progression from normal gland to adenomas which persisted on the same level at the subsequent stages of malignancy. Nine proteins followed the carcinoma pattern with an up- or down-regulation between adenomas and carcinomas. The majority of 20 proteins followed the metastasis pattern with a significant change of protein expression levels between nonmetastatic and metastatic carcinomas. The present study therefore shows that differences in malignancy are associated with a stepwise but not linear change in protein expression levels, which does not finally confirm or disapprove the existence of a malignant progression in canine mammary tumors. In addition, the acquisition of metastatic potential seems to be associated with the strongest changes in protein expression levels.     

HGF／SF-Met signaling in tumor progression

Tumor progression is a multi-step process that requires a sequential selection of specific malignant phenotypes. Met activation may induce different phenotypes depending on tumor stage: inducing proliferation and angiogenesis in primary tumors, stimulating motility to form micrometastases, and regaining the proliferation phenotype to form overt metastases. To study how HGF/SF-induced proliferative phenotypes switch to the invasive phenotype is important for understanding the mechanism of tumor progression and will provide an attractive target for cancer intervention and therapy.     

Growth factors: a role in guiding axons?

A remarkable finding to emerge in recent years is that the early brain neuroepithelium is highly patterned before axonogenesis begins. Growth factors are among a variety of classes of molecules whose regionalized expression divides the early brain into molecularly distinct domains. Thus, when axons first grow to their synaptic targets, growth factor signalling may help them to navigate. This review discusses recent studies that reveal that growth factors can act as chemoattractants and repellents and that growth factor signalling is important for target entry. These new findings raise the compelling idea that growth factors play an active role in axon navigation.     

Photoentrainment in mammals: a role for cryptochrome?

There is growing evidence in support of the hypothesis that, in mammals, photoreceptive tasks are segregated into those associated with creating a detailed visual image of the environment and those involved in the photic regulation of temporal biology. The hypothesis that this segregation extends to the use of different photoreceptors remains unproven, but published reports from several mammalian species that circadian photoentrainment survives a degree of retinal degeneration sufficient to induce visual blindness suggest that this may be so. This has lead to speculation that mammals might employ a dedicated 'circadian photoreceptor' distinct from the rod and cone cells of the visual system. The location and nature of this putative circadian photoreceptor has become a matter of conjecture. The latest candidates to be put forward as potential circadian photopigments are the mammalian cryptochrome proteins (CRY1 and 2), putative vitamin-B2 based photopigments. To date, published experimental evidence falls short of a definitive demonstration that these proteins form the basis of circadian photoreception in mammals. Consequently, this review aims to assess their suitability for this task in light of what we know regarding the biology of the cyrptochromes and the nature of mammalian photoentrainment.     

Autophagy: a role in metal ion homeostasis?

Nutrient limitation is one of the most common forms of stress encountered by microorganisms in the environment. Surviving this stress depends upon a number of integrated responses, one of the most important of which is autophagy. When the filamentous fungus Aspergillus fumigatus becomes nutrient deprived it undergoes two important processes: the developmental pathway for asexual sporulation (conidiation), and a foraging response that promotes the migration of the hyphal tips into new substrate. To determine the contribution of autophagy to these two functions, we disrupted the A. fumigatus atg1 gene. The data reveal that Atg1 is required for wild-type conidiation of A. fumigatus, but only when nitrogen is limiting. Secondly, we demonstrate that metal ion availability limits the extent to which A. fumigatus can grow without a carbon/nitrogen source and that autophagy is necessary for growth under conditions of metal ion deficiency. These findings indicate that autophagy is responsible for maintaining an adequate supply of nitrogen to support conidiophore development, and provide intriguing new evidence that autophagy is linked to metal ion homeostasis.