Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth

Little progresses have been made in the treatment of glioblastoma (GBM), the most aggressive and lethal among brain tumors. Recently we have demonstrated that Chloride Intracellular Channel-1 (CLIC1) is overexpressed in GBM compared to normal tissues, with highest expression in patients with poor prognosis. Moreover, CLIC1-silencing in cancer stem cells (CSCs) isolated from human GBM patients negatively influences proliferative capacity and self-renewal properties in vitro and impairs the in vivo tumorigenic potential. Here we show that CLIC1 exists also as a circulating protein, secreted via extracellular vesicles (EVs) released by either cell lines or GBM-derived CSCs. Extracellular vesicles (EVs), comprising exosomes and microvesicles based on their composition and biophysical properties, have been shown to sustain tumor growth in a variety of model systems, including GBM. Interestingly, treatment of GBM cells with CLIC1-containing EVs stimulates cell growth both in vitro and in vivo in a CLIC1-dose dependent manner. EVs derived from CLIC1-overexpressing GBM cells are strong inducers of proliferation in vitro and tumor engraftment in vivo. These stimulations are significantly attenuated by treatment of GBM cells with EVs derived from CLIC1-silenced cells. However, CLIC1 modulation appears to have no direct role in EV structure, biogenesis and secretion. These findings reveal that, apart from the function of CLIC1 cellular reservoir, CLIC1 contained in EVs is a novel regulator of GBM growth

Role of Rai/Shc C proteins in adult neural stem cells and progenitors

Rationale. Rai-/- mice are less resistant to ischemic damage compared to the wild type mice. They show increased mortality and more neuronal apoptosis. This phenotype can be explained only in part with Rai-induced survival in mature neurons. In the last years neural stem cells (NSC) have been shown to play an essential role in the recovery of the brain upon ischemia, through their mobilization, migration toward the damaged site and induction of de novo neurogenesis to replace dead neurons. Aim of the project. We therefore asked whether Rai was expressed in the adult neural stem cells and whether it could have a role in adult neurogenesis. Results. Taking advantage of wild type and Rai-/- mice, we isolated adult neural stem cells from the subventricular zone of the brain and cultured them as neurospheres. We found that Rai is expressed in adult neural stem cells and progenitors, and that a lack of Rai proteins results in an impaired differentiation, with a lower number of neurons, which are also less mature. The absence of Rai also causes an impaired NSC/progenitor migration. The investigation of the signalling mechanisms responsible for these phenotypes revealed that in Rai-/- neurospheres there is a defect in the Wnt/β-catenin pathway activation. We observed that in the absence of Rai casein kinase I activity is enhahanced and β-catenin is hyperphosphorylated, resulting in β-catenin failure to enter the nucleus and activate the transcription of target genes specifically involved in neurogenesis. With this work we describe for the first time a role for Rai in adult neurogenesis through activation of the Wnt/β-catenin pathway. Rai proved to favour both neuronal differentiation and migration of NSC/progenitors, two essential components of neurogenesis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Svensk Botanisk Tidskrift : Volym 53: Häfte 3, 1959

INNEHÅLLSFÖRTECKNING. E. WIKBERG: Studies on Biochemical Mutations in Ophiostoma with Special Reference to Some Pyridoxamine-deficient Strains. F. FAGERLIND: Development and Structure of the Flower and Gametophytes in the Genus Exocarpos. L. BOO: Effect of Gibberellin on the Growth in Length of Polyploids. S. SUNESON: Lemna gibba i Bohuslän. K. V. OSSIAN DAHLGREN: Propf- und Vererbungsversuche mit Fragaria vesca f. micrantha. W. A. WEBER and S. SHUSHAN: Lichens of the Queen Charlotte Islands, Collected in 1957 by Dr. Herman Persson. N. HYLANDER: Om förekomsten av Phyteuma nigrum i Medelpad och om några nyare nordiska fynd av denna art. H. RUFELT: Influence of Coumarin on Geotropisin and Growth of Wheat Roots. RECENSIONER: ERIC HULTÉN: N. Polunin; Circumpolar Arctic Flora. KARL AFZELIUS: Carl L. Withner; The Orchids. A Scientific Survey. A. VEGIS: Handbuch der Pflanzenphysiologie, herausgegeben von W. Ruhland. Band VII. T. HEMBERG: Bruno Huber; Die Saftströme der Pflanzen. G. ERDTMAN: H. Freund; Handbuch der Mikroskopie in der Technik, Bd II: 3. F. Kirchheimer; Die Laubgewächse der Braunkohlenzeit. B. SPARRE: Curt Backeberg; Die Cactaceae. Handbuch der Kakteenkunde. Band II. B. SPARRE: H. St. John; Nomenclature of Plants. S. AHLNER: Verne Grant; Natural History of the Phlox Family. I. Systematic Botany. S. AHLNER: Carolus Linnaeus; Species Plantarum (1753). Facsimile, Vol. II. S. AHLNER: Hans Pitschmann, Herbert Reisigl und Hugo Schiechtl; Bilder-Flora der Südalpen vom Gardasee zum Comersee. S. AHLNER: A. R. Clapham, T. G. Tutin and E. F. Warburg; Excursion Flora of the British Isles. S. AHLNER: Matthias Riehl; Orchids. J. A. NANNFELDT: Flora ČSR. B 1. Gasteromycetes. Red. A. Pilát

The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.

Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade

The adaptor protein Rai/ShcC promotes astrocyte-dependent inflammation during experimental autoimmune encephalomyelitis

Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model.We found that, unexpectedly, EAE was less severe in Rai2/2 mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai+/+ mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis