Matrix metalloproteinases in tumorigenesis: an evolving paradigm

Proteases are crucial for development, tissue remodeling, and tumorigenesis. Matrix metalloproteinases (MMPs) family, in particular, consists of more than 20 members with unique substrates and diverse function. The expression and activity of MMPs in a variety of human cancers have been intensively studied. MMPs have well-recognized roles in the late stage of tumor progression, invasion, and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis, e.g., in malignant transformation, angiogenesis, and tumor growth both at the primary and metastatic sites. Recent studies also suggest that MMPs play complex roles in tumor progression. While most MMPs promote tumor progression, some of them may protect the host against tumorigenesis in a context-dependent manner. MMPs have been chosen as promising targets for cancer therapy on the basis of their aberrant up-regulation in malignant tumors and their ability to promote cancer metastasis. Although preclinical studies testing the efficacy of MMP suppression in tumor models were so encouraging, the results of clinical trials in cancer patients have been rather disappointing. Here, we review the complex roles of MMPs and their endogenous inhibitors such as tissue inhibitors of metalloproteinase in tumorigenesis and strategies in suppressing MMPs.     

Nuclear apparatus and binary fission inSpirostomum dharwarensis n. sp.

Résumé Dans cet article on a décrit l'appareil nucléaire et la fission binaire dans le cilié d'eau douceSpirostomum dharwarensis. La division micronucléaire est de type synchrone. En ce qui concerne le mode de division micronucléaire, on a étudié également le déplacement graduel du type sélectif au type synchrone dans le genreSpirostomum.     

Platelets and viruses: an ambivalent relationship

Thrombocytopenia is a frequent complication of viral infections providing evidence that interaction of platelets with viruses is an important pathophysiological phenomenon. Multiple mechanisms are involved depending on the nature of the viruses involved. These include immunological platelet destruction, inappropriate platelet activation and consumption, and impaired megakaryopoiesis. Viruses bind platelets through specific receptors and identified ligands, which lead to mutual alterations of both the platelet host and the viral aggressor. We have shown that HIV-1 viruses are internalized specifically in platelets and megakaryocytes, where they can be either sheltered, unaltered (with potential transfer of the viruses into target organs), or come in contact with platelet secretory products leading to virus destruction and facilitated platelet clearance. In this issue, we have reviewed the various pathways that platelets use in order to interact with viruses, HIV and others. This review also shows that more work is still needed to precisely identify platelet roles in viral infections, and to answer the challenge of viral safety in platelet transfusion.     

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

From a handful of uncloned genetic loci 6 years ago, great strides have been made in understanding the genetic and molecular aetiology of Bardet-Biedl syndrome (BBS), a rare pleiotropic disorder characterised by a multitude of symptoms, including obesity, retinal degeneration and cystic kidneys. Presently, 11 BBS genes have been cloned, with the likelihood that yet more BBS genes remain undiscovered. In 2003, a major breakthrough was made when it was shown that BBS is likely caused by defects in basal bodies and/or primary cilia. Since then, studies in numerous animal models of BBS have corroborated the initial findings and, in addition, have further refined the specific functions of BBS proteins. These include roles in establishing planar cell polarity (noncanonical Wnt signaling) in mice and zebrafish, modulating intraflagellar transport and lipid homeostasis in worms, and regulating intracellular trafficking and centrosomal functions in zebrafish and human tissue culture cells. From these discoveries, a common theme has emerged, namely that the primary function of BBS proteins may be to mediate and regulate microtubule-based intracellular transport processes. Received 20 April 2006; received after revision 30 May 2006; accepted 15 June 2006     

The mitotic chromosomes of the lampreyMordacia mordax (agnatha: Petromyzonidae)

Résumé L'étude des chromosomes somatiques de la lamproie de l'hémisphère sud,Mordacia mordax (Richardson), montre que l'équipement chromosomique diploïde de cette espèce est composé de 76 chromosomes très petits. La plupart des chromosomes sont métacentrique ou bien submétacentrique. Ces chromosomes sont différents en nombre de ceux décrits pour les lamproies de l'hémisphère nord.     

Nematodes and the spleen: An immunological relationship

Despite being a major organ of the immune system, the spleen's role in resisting, controlling or simply ameliorating nematode infections has been neglected. A review of both filarial and gastrointestinal nematodes suggests that though it is difficult to fully assess or quantify the organ's importance in vivo, the spleen is prominent in acting against nematode parasites in mammals. One manifestation of this is that transfer of lymphocytes from the spleen of immunised individuals can protect recipients against the disease. Expansion of splenic lymphoid tissue also alludes to its activity during nematode infection. There is a considerable need for investigation of the spleen under natural conditions as well as much more rigorously controlled experiments even in mammals besides birds and other vertebrates.     

Nematodes and the spleen: An immunological relationship

Despite being a major organ of the immune system, the spleen's role in resisting, controlling or simply ameliorating nematode infections has been neglected. A review of both filarial and gastrointestinal nematodes suggests that though it is difficult to fully assess or quantify the organ's importance in vivo, the spleen is prominent in acting against nematode parasites in mammals. One manifestation of this is that transfer of lymphocytes from the spleen of immunised individuals can protect recipients against the disease. Expansion of splenic lymphoid tissue also alludes to its activity during nematode infection. There is a considerable need for investigation of the spleen under natural conditions as well as much more rigorously controlled experiments even in mammals besides birds and other vertebrates.     

Nuclear envelope and nuclear matrix: interactions and dynamics

The peripheral nuclear lamina is located near the nuclear inner membrane and consists of lamin filaments and integral membrane proteins, including the lamin B receptor and various isoforms of lamina-associated polypeptides (LAP) 1 and 2. Several nuclear membrane proteins also interact with chromatin proteins BAF and Hp1. Lamins in the nuclear interior associate with at least one soluble (non-membrane-bound) LAP2 isoform named LAP2alpha. The internal lamins, together with Tpr-based filaments that connect to nuclear pore complexes, are proposed to be major structural elements of the internal nuclear matrix. We describe the structural links between the peripheral lamina and the internal nuclear matrix that are thought to be mediated by LAP2 family members, filament protein Tpr and nucleoporin Nup153. These findings are discussed in relation to human diseases that arise from mutations in nuclear lamina proteins.     

Repetitive order and the human walking apparatus: Prussian military science versus the Webers' locomotion research

The addition of 'fire' to the European battle repertoire resulted in the close-order drill for manoeuvres of the line. Begun in late sixteenth-century Netherlands and perfected in eighteenth-century Prussia under Frederick the Great, the drill's precision marching evolved into a military science which conceived what infantry acquired through rigorous training as a lawful 'second nature' of men. In contrast, the liberal Webers' 1836 locomotion research orientation was, as was that of French skirmishing, one of natural self-regulation. Later Prussian military science, restored in Imperial Germany, was merged into locomotion science.     

Tissue transglutaminase inhibits the TRPV5-dependent calcium transport in an N-glycosylation-dependent manner

Tissue transglutaminase (tTG) is a multifunctional Ca²⁺-dependent enzyme, catalyzing protein crosslinking. The transient receptor potential vanilloid (TRPV) family of cation channels was recently shown to contribute to the regulation of TG activities in keratinocytes and hence skin barrier formation. In kidney, where active transcellular Ca²⁺ transport via TRPV5 predominates, the potential effect of tTG remains unknown. A multitude of factors regulate TRPV5, many secreted into the pro-urine and acting from the extracellular side. We detected tTG in mouse urine and in the apical medium of polarized cultures of rabbit connecting tubule and cortical collecting duct (CNT/CCD) cells. Extracellular application of tTG significantly reduced TRPV5 activity in human embryonic kidney cells transiently expressing the channel. Similarly, a strong inhibition of transepithelial Ca²⁺ transport was observed after apical application of purified tTG to polarized rabbit CNT/CCD cells. Furthermore, tTG promoted the aggregation of the plasma membrane-associated fraction of TRPV5. Using patch clamp analysis, we observed a reduction in the pore diameter after tTG treatment, suggesting distinct structural changes in TRPV5 upon crosslinking by tTG. As N-linked glycosylation of TRPV5 is a key step in regulating channel function, we determined the effect of tTG in the N-glycosylation-deficient TRPV5 mutant. In the absence of N-linked glycosylation, TRPV5 was insensitive to tTG. Taken together, these observations imply that tTG is a novel extracellular enzyme inhibiting the activity of TRPV5. The inhibition of TRPV5 occurs in an N-glycosylation-dependent manner, signifying a common final pathway by which distinct extracellular factors regulate channel activity.     

Lumping,testing, tuning: The invention of an artificial chemistry in atmospheric transport modeling

Since the late 1950s computer simulation has been used to investigate the transport of pollutants in the atmosphere. About 20 years later also the chemical transformation of atmospheric pollutants was included in computer models of photochemical smog formation. Due to limited knowledge of atmospheric chemistry and due to limited computer capacity, chemical processes in the atmosphere were modeled with the help of simplified chemical models. In these models chemical substances are lumped together forming artificial virtual compounds with virtual characteristics. The paper aims at studying the practices developed in chemical model building and the creation of confidence in these models. Core of the paper will be the analysis of the Urban Airshed Model (UAM) for the Los Angeles region, a pioneering development in the early 1970s. The construction of the UAM involved the “lumping” of chemical processes and extensive testing and tuning. These practices led to a consistent model representation, in which diverse pieces of information fitted and were mutually stabilized. The pragmatic achievement of consistency created confidence, even though empirical tests of the models remained ambiguous and problematic.     

Melatonin and the electron transport chain

Melatonin protects the electron transport chain (ETC) in multiple ways. It reduces levels of ·NO by downregulating inducible and inhibiting neuronal nitric oxide synthases (iNOS, nNOS), thereby preventing excessive levels of peroxynitrite. Both ·NO and peroxynitrite-derived free radicals, such as ·NO₂, hydroxyl (·OH) and carbonate radicals (CO₃·^?) cause blockades or bottlenecks in the ETC, by ·NO binding to irons, protein nitrosation, nitration and oxidation, changes that lead to electron overflow or even backflow and, thus, increased formation of superoxide anions (O₂·^?). Melatonin improves the intramitochondrial antioxidative defense by enhancing reduced glutathione levels and inducing glutathione peroxidase and Mn-superoxide dismutase (Mn-SOD) in the matrix and Cu,Zn-SOD in the intermembrane space. An additional action concerns the inhibition of cardiolipin peroxidation. This oxidative change in the membrane does not only initiate apoptosis or mitophagy, as usually considered, but also seems to occur at low rate, e.g., in aging, and impairs the structural integrity of Complexes III and IV. Moreover, elevated levels of melatonin inhibit the opening of the mitochondrial permeability transition pore and shorten its duration. Additionally, high-affinity binding sites in mitochondria have been described. The assumption of direct binding to the amphipathic ramp of Complex I would require further substantiation. The mitochondrial presence of the melatonin receptor MT₁ offers the possibility that melatonin acts via an inhibitory G protein, soluble adenylyl cyclase, decreased cAMP and lowered protein kinase A activity, a signaling pathway shown to reduce Complex I activity in the case of a mitochondrial cannabinoid receptor.     

Arresting the mitotic oscillator and the control of cell proliferation: insights from a cascade model for cdc2 kinase activation

We consider a minimal cascade model previously proposed¹¹ for the mitotic oscillator driving the embryonic cell division cycle. The model is based on a bicyclic phosphorylation-dephosphorylation cascade involving cyclin and cdc2 kinase. By constructing stability diagrams showing domains of periodic behavior as a function of the maximum rates of the kinases and phosphatases involved in the two cycles of the cascade, we investigate the role of these converter enzymes in the oscillatory mechanism. Oscillations occur when the balance of kinase and phosphatase rates in each cycle is in a range bounded by two critical values. The results suggest ways to arrest the mitotic oscillator by altering the maximum rates of the converter enzymes. These results bear on the control of cell proliferation.