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Cabodi S.,University of Turin | Tinnirello A.,University of Turin | Bisaro B.,University of Turin | Tornillo G.,University of Turin | And 12 more authors.
FASEB Journal | Year: 2010

The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers. © FASEB.

Pierobon D.,University of Turin | Raggi F.,Ggaslini Institute | Cambieri I.,Burns Center and Skin Bank | Pelassa S.,Ggaslini Institute | And 11 more authors.
Journal of Molecular Medicine | Year: 2016

Abstract: Langerhans cells (LCs) are a specialized dendritic cell subset that resides in the epidermis and mucosal epithelia and is critical for the orchestration of skin immunity. Recent evidence suggest that LCs are involved in aberrant wound healing and in the development of hypertrophic scars and chronic wounds, which are characterized by a hypoxic environment. Understanding LCs biology under hypoxia may, thus, lead to the identification of novel pathogenetic mechanisms of wound repair disorders and open new therapeutic opportunities to improve wound healing. In this study, we characterize a previously unrecognized role for hypoxia in significantly affecting the phenotype and functional properties of human monocyte-derived LCs, impairing their ability to stimulate naive T cell responses, and identify the triggering receptor expressed on myeloid (TREM)-1, a member of the Ig immunoregulatory receptor family, as a new hypoxia-inducible gene in LCs and an activator of their proinflammatory and Th1-polarizing functions in a hypoxic environment. Furthermore, we provide the first evidence of TREM-1 expression in vivo in LCs infiltrating hypoxic areas of active hypertrophic scars and decubitous ulcers, pointing to a potential pathogenic role of this molecule in wound repair disorders. Key messages: Hypoxia modulates surface molecule expression and cytokine profile in Langerhans cells.Hypoxia impairs human Langerhans cell stimulatory activity on naive T cells.Hypoxia selectively induces TREM-1 expression in human Langerhans cells.TREM-1 engagement stimulates Langerhans cell inflammatory and Th1-polarizing activity.TREM-1 is expressed in vivo in Langerhans cells infiltrating hypoxic skin lesions. © 2016 Springer-Verlag Berlin Heidelberg

Zucca C.,R.O.S.A. | Zanotta N.,R.O.S.A. | Epifanio R.,R.O.S.A. | Redaelli F.,Laboratorio Of Biologia Molecolare | Bassi M.T.,Laboratorio Of Biologia Molecolare
Bollettino - Lega Italiana contro l'Epilessia | Year: 2010

We report a family with a novel SCN1A mutation segregating in the proband and inherited from the paternal line. The proband had West syndrome (WS) in infancy, and later developed Lennox Gastaut syndrome (LGS). In the paternal line, there is only one affected member who had febrile seizures Epileptic phenotype was also present in the maternal line. We thus hypothesize a complex system of genetic expression with possible involvement of other genes. SCN1A mutations have been occasionally associated with LGS, but this is the first report of an association with WS.

Costa C.,University of Perugia | Prontera P.,Sezione di Genetica Medica | Prontera P.,University of Perugia | Sarchielli P.,University of Perugia | And 7 more authors.
Cephalalgia | Year: 2014

Background: Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fully reversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A, ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy. Case: Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causing guanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine, four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalized epilepsy with febrile seizures plus (GEFS+). Conclusions: The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine and epilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders. © International Headache Society 2013.

Magnani A.,Laboratorio Of Biologia Molecolare | Pattacini L.,Laboratorio Of Biologia Molecolare | Boiardi L.,Unita Operativa di Reumatologia | Casali B.,Laboratorio Of Biologia Molecolare | Salvarani C.,Unita Operativa di Reumatologia
Clinical and Experimental Rheumatology | Year: 2010

Objectives: To evaluate the presence and the glycosylation pattern of reelin in synovial fluid and serum of patients affected by different rheumatic pathologies. Methods: Reelin levels were evaluated in patients affected by rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA) and osteoarthritis (OA). Reelin semi-quantitative assays were performed by western blot. The glycosylation pattern was evaluated by immunoblotting performed by sepharose conjugated lectins. RT-PCR was used to detect the presence of mRNA encoding for reelin and its receptors. Results: Reelin is detectable in both sinovial fluids and sera and its levels are more elevated in patients affected by RA with respect to those affected by other inflammatory and non inflammatory joint diseases. The glycosylation pattern of the protein differs in synovial fluid and serum. Fibroblast-like synoviocytes (FLS) express the mRNAs encoding for reelin and its receptors. Conclusions: Since its levels are higher in RA then in the other analysed pathologies, reelin can represent a candidate suitable for the differential diagnosis of this pathology. Moreover, the observation that this protein is encoded by FLS and differentially glycosylated in blood and synovial fluid supports the hypothesis that it is locally produced in the joints, where it could play an important role in RA development and maintenance. © clinical and experimental rheumatology 2010.

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