Shinohara ML, Kim HJ, Kim JH, Garcia VA, Cantor H.. Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells. Proc Natl Acad Sci U S A 105: 7235-7239

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2008; 105(20):7235-9. DOI: 10.1073/pnas.0802301105
Source: PubMed


Osteopontin (Opn) contributes to diverse biological processes that include immune responses, vascularization, and bone formation. Until recently, studies describing the activities of Opn have focused on the cytokine-like properties of the secreted protein. Here, we show that alternative translation of a single Opn mRNA species generates a secreted and intracellular isoform. Utilization of a 5' canonical translation start site generates a protein that includes an N-terminal signal sequence allowing targeting to secretory vesicles and cytokine secretion, whereas usage of a downstream start site generates a shortened protein that lacks the N-terminal signal sequence and localizes mainly to cytoplasm. The coordinated action of these Opn gene products regulates the functional phenotype of subsets of dendritic cells.

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    • "Due to common functional motifs and domains these five integrin-binding glycophosphoproteins are categorized as the so called SIBLING proteins (small integrin-binding ligand N-linked glycoproteins) [8]. OPN is encoded by a single copy gene, but exists in various isoforms as a result of alternative splicing, alternative translation and different posttranslational modifications (PTMs), which allow for a molecular weight ranging from 41 to 75 kDa [9–13]. To date three splice variants of the human OPN transcript have been identified: OPN a, the full-length isoform; OPN b which lacks exon 5 and OPN c which lacks exon 4 [11]. "
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    ABSTRACT: Since its first description more than 20 years ago osteopontin has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling and inflammation. As an extracellular matrix protein and proinflammatory cytokine osteopontin is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by osteopontin has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance. Here we summarize recent findings on the role of osteopontin in metabolic disorders, particularly focusing on diabetes and obesity.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.03.004
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    • "The finding that tumor OPN expression, but not serum OPN level, was associated with poor survival may be explained by the multi-functionality of OPN. The majority of the activities of OPN have been ascribed the interaction between secreted OPN and its receptors on target cells [27], however OPN is also found intracellularly and the nonsecreted form is involved in cellular processes such as migration and motility [27,28]. Our results may indicate that the intracellular levels of OPN are more important than the secreted circulating levels in NSCLC. "
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    ABSTRACT: In a previously published report we characterized the expression of the metastasis-associated proteins S100A4, osteopontin (OPN) and ephrin-A1 in a prospectively collected panel of non-small cell lung cancer (NSCLC) tumors. The aim of the present follow-up study was to investigate the prognostic impact of these potential biomarkers in the same patient cohort. In addition, circulating serum levels of OPN were measured and single nucleotide polymorphisms (SNP) in the -443 position of the OPN promoter were analyzed. Associations between immunohistochemical expression of S100A4, OPN and ephrin-A1 and relapse free and overall survival were examined using univariate and multivariate analyses. Serum OPN was measured by ELISA, polymorphisms in the -443 position of the tumor OPN promoter were analyzed by PCR, and associations between OPN levels and promoter polymorphisms and clinicopathological parameters and patient outcome were investigated. High expression of OPN in NSCLC tumors was associated with poor patient outcome, and OPN was a strong, independent prognostic factor for both relapse free and overall survival. Serum OPN levels increased according to tumor pT classification and tumor size, and patients with OPN-expressing tumors had higher serum levels than patients with OPN-negative tumors. S100A4 was a negative prognostic factor in several subgroups of adenocarcinoma patients, but not in the overall patient cohort. There was no association between ephrin-A1 expression and patient outcome. OPN is a promising prognostic biomarker in NSCLC, and should be further explored in the selection of patients for adjuvant treatment following surgical resection.
    BMC Cancer 11/2013; 13(1):540. DOI:10.1186/1471-2407-13-540 · 3.36 Impact Factor
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    • "In our study, the cytoplasmic expression was dominant than nuclear expression in all tissues examined from normal to malignant tumours. Previously, OPN was shown to be perimembranous and cytoplasmic [34] [35] [36]. In thyroid cancers , only cytoplasmic localisation was reported and one study reported a cytoplasmic and membranous localisation [23]. "
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    ABSTRACT: Background: Osteopontin (OPN) is expressed in various malignancies and may play an important role in tumorigenesis, tumour invasion, and metastasis in various malignancies including thyroid cancers. The objective of this study was to investigate the relationship between OPN immunoexpression and clinicopathological characteristics in thyroid lesions. Material and methods: Paraffin blocks belonging to 160 patients with thyroid neoplasms were retrieved from the archive of the Department of Pathology at King Abdulaziz University, and King Faisal Specialist Hospital, Jeddah, Saudi Arabia. Immunohistochemistry was performed using anti-OPN antibody. Statistical tests were used to determine the relation of OPN immunoexpression to clinicopathological characteristics and survival. Results: Immunostaining results showed that OPN was localised in the cytoplasm and nucleus with higher cytoplasmic expression. Cytoplasmic and nuclear OPN was higher in thyroid cancer than other lesions. Microcarcinoma variant of papillary thyroid carcinoma showed a lower OPN cytoplasmic level than other variants. OPN cytoplasmic expression was not associated with most of the clinicopathological parameters tests. However, OPN cytoplasmic overexpression was associated poor survival outcome (p < 0.001). Conclusion: Upregulation of cytoplasmic OPN was associated with poor survival outcome and was an independent predictor of margin involvement and recurrence. Nuclear OPN expression was lower than cytoplasmic and was associated with extrathyroid extension of thyroid cancer. OPN plays a role in thyroid carcinoma and incoming research has to be focused on the mechanistic association with invasion and metastasis.
    09/2013; 1(1-2):8-16. DOI:10.1016/j.jmau.2013.07.001
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