Caprin-1, a novel Cyr61-interacting protein, promotes osteosarcoma tumor growth and lung metastasis in mice

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. More than 30% of patients develop lung metastasis, which is the leading cause of mortality. Recently, the extracellular matrix protein Cyr61 has been recognized as a malignancy promoting protein in OS mouse model with prognostic potential in human OS. In this study, we aimed at the identification of novel Cyr61-interacting proteins. Here we report that Cyr61 associates with Caprin-1, and confocal microscopy showed that stable ectopic expression of Caprin-1 leads to the formation of stress granules containing Caprin-1 and Cyr61, confers resistance to cisplatin-induced apoptosis, and resulted in constitutive phosphorylation of Akt and ERK1/2. Importantly, ectopic expression of Caprin-1 dramatically enhanced primary tumor growth, remarkably increased lung metastatic load in a SCID intratibial OS mouse model, and decreased significantly (p<0.0018) the survival of the mice. Although Caprin-1 expression, evaluated with a tissue microarray including samples from 59 OS patients, failed to be an independent predictor for the patients' outcome in this limited cohort of patients, increased Caprin-1 expression indicated a tendency to shortened overall survival, and more strikingly, Cyr61/Caprin-1 co-expression was associated with worse survival than that observed for patients with tumors expressing either Cyr61 or Caprin-1 alone or none of these proteins. The findings imply that Caprin-1 may have a metastasis promoting role in OS and show that through resistance to apoptosis and via the activation of Akt and ERK1/2 pathways, Caprin-1 is significantly involved in the development of OS metastasis

Drug-induced stress granule formation protects sensory hair cells in mouse cochlear explants during ototoxicity

Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases.EI:595 - Action on Hearing Loss; 091092/Z/09/Z - Wellcome Trust (Wellcome); MR/N004329/1 - RCUK | Medical Research Council (MRC)Published versio

RNA binding protein Caprin-2 is a pivotal regulator of the central osmotic defense response

In response to an osmotic challenge, the synthesis of the antidiuretic hormone arginine vasopressin (AVP) increases in the hypothalamus, and this is accompanied by extension of the 3′ poly(A) tail of the AVP mRNA, and the up-regulation of the expression of RNA binding protein Caprin-2. Here we show that Caprin-2 binds to AVP mRNAs, and that lentiviral mediated shRNA knockdown of Caprin-2 in the osmotically stimulated hypothalamus shortens the AVP mRNA poly(A) tail at the same time as reducing transcript abundance. In a recapitulated in vitro system, we confirm that Caprin-2 over-expression enhances AVP mRNA abundance and poly(A) tail length. Importantly, we show that Caprin-2 knockdown in the hypothalamus decreases urine output and fluid intake, and increases urine osmolality, urine sodium concentration, and plasma AVP levels. Thus Caprin-2 controls physiological mechanisms that are essential for the body's response to osmotic stress. DOI: http://dx.doi.org/10.7554/eLife.09656.00

Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation

The low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6) are coreceptors for Frizzled and transmit signals from the plasma membrane to the cytosol. However, the mechanism for LRP5/6 signal transmission remains undefined. Here, we identify cytoplasmic activation/proliferation-associated protein 2 (Caprin-2) as a LRP5/6-binding protein. Our data show that Caprin-2 stabilizes cytosolic β-catenin and enhances lymphoid enhancer-binding factor 1/T cell factor–dependent reporter gene activity as well as the expression of Wnt target genes in mammalian cells. Morpholino-mediated knockdown of Caprin-2 in zebrafish embryos inhibits Wnt/β-catenin signaling and results in a dorsalized phenotype. Moreover, Caprin-2 facilitates LRP5/6 phosphorylation by glycogen synthase kinase 3, and thus enhances the interaction between Axin and LRP5/6. Therefore, Caprin-2 promotes activation of the canonical Wnt signaling pathway by regulating LRP5/6 phosphorylation

Mio-Pliocene Faunal Exchanges and African Biogeography: The Record of Fossil Bovids

The development of the Ethiopian biogeographic realm since the late Miocene is here explored with the presentation and review of fossil evidence from eastern Africa. Prostrepsiceros cf. vinayaki and an unknown species of possible caprin affinity are described from the hominid-bearing Asa Koma and Kuseralee Members (∼5.7 and ∼5.2 Ma) of the Middle Awash, Ethiopia. The Middle Awash Prostrepsiceros cf. vinayaki constitutes the first record of this taxon from Africa, previously known from the Siwaliks and Arabia. The possible caprin joins a number of isolated records of caprin or caprin-like taxa recorded, but poorly understood, from the late Neogene of Africa. The identification of these two taxa from the Middle Awash prompts an overdue review of fossil bovids from the sub-Saharan African record that demonstrate Eurasian affinities, including the reduncin Kobus porrecticornis, and species of Tragoportax. The fossil bovid record provides evidence for greater biological continuity between Africa and Eurasia in the late Miocene and earliest Pliocene than is found later in time. In contrast, the early Pliocene (after 5 Ma) saw the loss of any significant proportions of Eurasian-related taxa, and the continental dominance of African-endemic taxa and lineages, a pattern that continues today

Lev Vygotskij, figura e opera da (ri)scoprire. Un contributo alle teorie dell’educazione

Dopo un’introduzione alla figura e al pensiero di Lev Vygotskij, se ne esaminano gli aspetti relativi alle influenze storico-culturali sulle modalità di funzionamento cognitivo umano, con attinenza alla psicologia dello sviluppo e dell’educazione, nonché alla didattica. Mentre, infatti, alcune delle sue osservazioni sono state inglobate all’interno di moderne teorie dell’apprendimento, nelle discipline più diverse, dall’insegnamento della lettura e della scrittura a quello della matematica, altre sono state utilizzate solo in modo parziale o inconsapevole; altre ancora restano da analizzare e mettere a frutto. Il contributo si pone l’obiettivo di delineare tali aspetti, e quindi di (ri)scoprire l’opera di Vygotskij, sempre attuale per quanto riguarda sia la comprensione delle dinamiche implicate nei processi di apprendimento sia lo sviluppo delle abilità cognitive umane, in un clima di cooperazione docente-discente, dove il ruolo del primo è fondamentale al fine della riuscita, nel compito, del secondo.After an introduction to the figure and thought of Lev Vygotskij, some features concerning historical and cultural influences on human cognitive functioning will be analysed, especially in relation to developmental and educational psychology and teaching. Among Vygotskij’s ideas, some have been incorporated into modern theories of learning in various disciplines, ranging from teaching reading and writing skills to mathematics; others have been only partially or casually employed; others still remain to be analysed and used. This contribution aims to outline these issues in order to (re)discover Vygotskij’s work. In fact, his thought remains central to both the understanding of the dynamics of the learning process and to the development of human cognitive abilities, especially in relation to teacher-learner cooperation. In fact, teachers have a fundamental role in order to make their students’activities successful

Diversification et intégration inter-specifique dans les élevages ruraux au Burkina Faso

Diversification and inter-species integration in rural livestock system in Burkina Faso. The purpose of this study was to determine the level of existing relation between several animal species bred in extensive livestock systems. Data were collected about breeding importance of cattle, sheep, goat and fowl in four villages of the central region of Burkina Faso (Namanegma, Villy-Moukouan, Luili-Nobere and Yambasse). These villages are located in the Soudano-Sahelian agroclimatic zone. Partial correlation and bivariate ordinary least square methods are computed. The results show that livestock practices are related to diversification and species integration strategies of rural households. That is, many households (16.64/) breed four species together, while 6.14/ of households possess one species. Three and two species breeders account for 14.95 and 14.36/ of households respectively. Poultry represents a driving activity in extensive livestock system. From a social welfare standpoint, fowl activity accounts for 49.42/ of households employment. Cattle breeding is the highest stage in this system and represents a kind ofsocioeconomic prestige for the breeder. The four types of livestock are correlated at different levels. Thus, high correlation degrees are noted between poultry and goat (p > 0.50). On the other hand, there is a weak relation between the remote livestock levels (e.g. poultry and cattle, p < 0.50). These results suggest that incentive policies for livestock must take into account breeders strategies. To promote poultry production can create track down effect on the entire livestock system