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Alternative splicing in the NF-kappaB signaling pathway.

ABSTRACT: Activation of transcription factor NF-kappaB can affect the expression of several hundred genes, many of which are involved in inflammation and immunity. The proper NF-kappaB transcriptional response is primarily regulated by post-translational modification of NF-kappaB signaling constituents. Herein, we review the accumulating evidence suggesting that alternative splicing of NF-kappaB signaling components is another means of controlling NF-kappaB signaling. Several alternative splicing events in both the tumor necrosis factor and Toll/interleukin-1 NF-kappaB signaling pathways can inhibit the NF-kappaB response, whereas others enhance NF-kappaB signaling. Alternative splicing of mRNAs encoding some NF-kappaB signaling components can be induced by prolonged exposure to an NF-kappaB-activating signal, such as lipopolysaccharide, suggesting a mechanism for negative feedback to dampen excessive NF-kappaB signaling. Moreover, some NF-kappaB alternative splicing events appear to be specific for certain diseases, and could serve as therapeutic targets or biomarkers.

SUBMITTER: Leeman JR

PROVIDER: S-EPMC2624576 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Alternative splicing in the NF-kappaB signaling pathway.

Leeman Joshua R JR Gilmore Thomas D TD

Gene 20080722 2

Activation of transcription factor NF-kappaB can affect the expression of several hundred genes, many of which are involved in inflammation and immunity. The proper NF-kappaB transcriptional response is primarily regulated by post-translational modification of NF-kappaB signaling constituents. Herein, we review the accumulating evidence suggesting that alternative splicing of NF-kappaB signaling components is another means of controlling NF-kappaB signaling. Several alternative splicing events i ...[more]

PMID: 18718859

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Project description:BackgroundThe prognosis of human glioma is poor, and the highly invasive nature of the disease represents a major impediment to current therapeutic modalities. The oncoprotein B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1) has been linked to the development and progression of glioma; however, the biological role of Bmi-1 in the invasion of glioma remains unclear.MethodsA172 and LN229 glioma cells were engineered to overexpress Bmi-1 via stable transfection or to be silenced for Bmi-1 expression using RNA interfering method. Migration and invasiveness of the engineered cells were assessed using wound healing assay, Transwell migration assay, Transwell matrix penetration assay and 3-D spheroid invasion assay. MMP-9 expression and activity were measured using real-time PCR, ELISA and the gelatin zymography methods. Expression of NF-kappaB target genes was quantified using real-time PCR. NF-kappaB transcriptional activity was assessed using an NF-kappaB luciferase reporter system. Expression of Bmi-1 and MMP-9 in clinical specimens was analyzed using immunohistochemical assay.ResultsEctopic overexpression of Bmi-1 dramatically increased, whereas knockdown of endogenous Bmi-1 reduced, the invasiveness and migration of glioma cells. NF-kappaB transcriptional activity and MMP-9 expression and activity were significantly increased in Bmi-1-overexpressing but reduced in Bmi-1-silenced cells. The reporter luciferase activity driven by MMP-9 promoter in Bmi-1-overexpressing cells was dependent on the presence of a functional NF-kappaB binding site, and blockade of NF-kappaB signaling inhibited the upregulation of MMP-9 in Bmi-1 overexpressing cells. Furthermore, expression of Bmi-1 correlated with NF-kappaB nuclear translocation as well as MMP-9 expression in clinical glioma samples.ConclusionsBmi-1 may play an important role in the development of aggressive phenotype of glioma via activating the NF-kappaB/MMP-9 pathway and therefore might represent a novel therapeutic target for glioma.

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Alternative splicing in the NF-kappaB signaling pathway.

Publications

Alternative splicing in the NF-kappaB signaling pathway.

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