Alternative translation of Osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2008; 105(20):7235-9. DOI: 10.1073/pnas.0802301105
Source: PubMed

ABSTRACT 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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Available from: Mari Shinohara, Jul 19, 2015
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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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    • "Here, we show that robust Th17 responses depended on the ability of a newly-defined translational intracellular isoform of Osteopontin (Shinohara et al., 2008) – Opn-i – to inhibit DC-dependent secretion of the potent inhibitory cytokine IL-27. IFNAR-dependent inhibition of Opn-i expression resulted in de-repression of IL-27 secretion and inhibition of the Th17 response in vitro and in vivo. "
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    ABSTRACT: Mechanisms that prevent inappropriate or excessive interleukin-17-producing T helper (Th17) cell responses after microbial infection may be necessary to avoid autoimmunity. Here, we define a pathway initiated by engagement of type I IFN receptor (IFNAR) expressed by dendritic cells (DC) that culminated in suppression of Th17 cell differentiation. IFNAR-dependent inhibition of an intracellular translational isoform of Osteopontin, termed Opn-i, derepressed interleukin-27 (IL-27) secretion and prevented efficient Th17 responses. Moreover, Opn-i expression in DC and microglia regulated the type and intensity of experimental autoimmune encephalomyelitis (EAE). Mice containing DC deficient in Opn-i produced excessive amounts of IL-27 and developed a delayed disease characterized by an enhanced Th1 response compared with the dominant Th17 response of Opn-sufficient mice. Definition of the IFNAR-Opn-i axis that controls Th17 development provides insight into regulation of Th cell sublineage development and the molecular basis of type I interferon therapy for MS and other autoimmune diseases.
    Immunity 08/2008; 29(1):68-78. DOI:10.1016/j.immuni.2008.05.008 · 19.75 Impact Factor
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